1,2,3-triazolo [4,3-a] pyridine derivatives and thier use for the treatment of prevention of neurological and psychiatric disorders

ABSTRACT

The present invention relates to novel triazolo[4,3- a ]pyridine derivatives of Formula (I) wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

FIELD OF THE INVENTION

The present invention relates to novel triazolo[4,3-a]pyridinederivatives which are positive allosteric modulators of the metabotropicglutamate receptor subtype 2 (“mGluR2”) and which are useful for thetreatment or prevention of neurological and psychiatric disordersassociated with glutamate dysfunction and diseases in which the mGluR2subtype of metabotropic receptors is involved. The invention is alsodirected to pharmaceutical compositions comprising such compounds, toprocesses to prepare such compounds and compositions, and to the use ofsuch compounds for the prevention or treatment of neurological andpsychiatric disorders and diseases in which mGluR2 is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino acid neurotransmitter in the mammaliancentral nervous system. Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration, and regulation of cardiovascular function. Furthermore,glutamate is at the centre of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptor channels (iGluRs), and the NMDA, AMPA andkainate receptors which are responsible for fast excitatorytransmission.

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This binding induces a conformational changein the receptor which results in the activation of the G-protein andintracellular signalling pathways.

The mGluR2 subtype is negatively coupled to adenylate cyclase viaactivation of Gαi-protein, and its activation leads to inhibition ofglutamate release in the synapse. In the central nervous system (CNS),mGluR2 receptors are abundant mainly throughout cortex, thalamicregions, accessory olfactory bulb, hippocampus, amygdala,caudate-putamen and nucleus accumbens.

Activating mGluR2 was shown in clinical trials to be efficacious totreat anxiety disorders. In addition, activating mGluR2 in variousanimal models was shown to be efficacious, thus representing a potentialnovel therapeutic approach for the treatment of schizophrenia, epilepsy,drug addiction/dependence, Parkinson's disease, pain, sleep disordersand Huntington's disease.

To date, most of the available pharmacological tools targeting mGluRsare orthosteric ligands which activate several members of the family asthey are structural analogues of glutamate.

A new avenue for developing selective compounds acting at mGluRs is toidentify compounds that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

It was demonstrated that such compounds do not activate the receptor bythemselves. Rather, they enable the receptor to produce a maximalresponse to a concentration of glutamate, which by itself induces aminimal response. Mutational analysis has demonstrated unequivocallythat the binding of mGluR2 positive allosteric modulators does not occurat the orthosteric site, but instead at an allosteric site situatedwithin the seven transmembrane region of the receptor.

Animal data suggest that positive allosteric modulators of mGluR2 haveeffects in anxiety and psychosis models similar to those obtained withorthosteric agonists. Allosteric modulators of mGluR2 were shown to beactive in fear-potentiated startle, and in stress-induced hyperthermiamodels of anxiety. Furthermore, such compounds were shown to be activein reversal of ketamine- or amphetamine-induced hyperlocomotion, and inreversal of amphetamine-induced disruption of prepulse inhibition of theacoustic startle effect models of schizophrenia.

Recent animal studies further reveal that the selective positiveallosteric modulator of metabotropic glutamate receptor subtype 2biphenyl-indanone (BINA) blocks a hallucinogenic drug model ofpsychosis, supporting the strategy of targeting mGluR2 receptors fortreating glutamatergic dysfunction in schizophrenia.

Positive allosteric modulators enable potentiation of the glutamateresponse, but they have also been shown to potentiate the response toorthosteric mGluR2 agonists such as LY379268 or DCG-IV. These dataprovide evidence for yet another novel therapeutic approach to treat theabove mentioned neurological and psychiatric diseases involving mGluR2,which would use a combination of a positive allosteric modulator ofmGluR2 together with an orthosteric agonist of mGluR2.

WO 2007/104783, WO 2008/107479 and WO 2009/033704 (Addex & JanssenPharmaceutica) describe pyridinone derivatives as mGluR2 positiveallosteric modulators. WO 2009/062676 (Addex & Janssen) published on 22Apr. 2009 discloses imidazopyridine derivatives as mGluR2 positiveallosteric modulators. The present triazolopyridine derivatives arecentrally active, potent compounds providing alternative mGluR2 positiveallosteric modulators with improved solubility and salt formingproperties.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds having metabotropic glutamatereceptor 2 modulator activity, said compounds having the Formula (I)

and the stereochemically isomeric forms thereof, wherein

-   n is selected from the group consisting of 0, 1 and 2;-   m is selected from the group consisting of 0, 1, and 2;-   R is selected from methyl or trifluoromethyl;-   R¹ is selected from the group consisting of hydrogen; C₁₋₆alkyl;    (C₁₋₃alkyloxy)-C₁₋₃alkyl; [(C₁₋₃alkyloxy)C₁₋₃alkyloxy]C₁₋₃alkyl;    C₁₋₃alkyl substituted with one or more independently selected halo    substituents; unsubstituted phenyl; unsubstituted benzyl; benzyl    substituted with 1, 2 or 3 substituents independently selected from    the group consisting of halo, C₁₋₃alkyl, C₁₋₃alkyloxy,    C₁₋₃alkyloxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl, cyano, hydroxyl, amino,    C(═O)R′, C(═O)OR′, C(═O)NR′R″, mono- or di(C₁₋₃alkyl)amino,    morpholinyl, (C₃₋₇cycloalkyl)C₁₋₃alkyloxy, trifluoromethyl and    trifluoromethoxy, wherein R′ and R″ are independently selected from    hydrogen and C₁₋₆alkyl; (benzyloxy)C₁₋₃alkyl; unsubstituted    C₃₋₇cycloalkyl; C₃₋₇cycloalkyl substituted with C₁₋₃alkyl    substituted with one or more independently selected halo    substituents; (C₃₋₇cycloalkyl)C₁₋₃alkyl;    [(C₃₋₇cycloalkyl)C₁₋₃alkyloxy]C₁₋₃alkyl;    (C₃₋₇cycloalkyl)C₁₋₃alkyloxy;    4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methyl; Het¹;    Het¹C₁₋₃alkyl; Het²; and Het²C₁₋₃alkyl;-   R² is selected from the group consisting of cyano; halo; C₁₋₃alkyl    substituted with one or more independently selected halo    substituents; C₁₋₃alkyloxy substituted with one or more    independently selected halo substituents; C₁₋₃alkyl; C₃₋₇cycloalkyl;    and (C₃₋₇cycloalkyl)C₁₋₃alkyl;

-   is an N-containing heterocycle selected from the group consisting of    (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L-h) below

-   wherein-   R^(3a) is selected from the group consisting of C₁₋₃alkyl; C₁₋₃alkyl    substituted with one or more independently selected halo    substituents; unsubstituted C₃₋₇cycloalkyl; C₃₋₇cycloalkyl    substituted with 1 or 2 substituents independently selected from    C₁₋₃alkyl, C₁₋₃alkyl substituted with one or more independently    selected halo substituents or hydroxyl; unsubstituted phenyl; phenyl    substituted with 1, 2 or 3 substituents independently selected from    the group consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, C₁₋₃alkyl    substituted with one or more independently selected halo    substituents, cyano, hydroxyl, amino, carboxyl,    C₁₋₃alkyloxy-C₁₋₃alkyl, C₁₋₃alkyloxy, C₁₋₃alkyloxy substituted with    one or more independently selected halo substituents,    C₁₋₃alkylcarbonyl, mono- and di(C₁₋₃alkyl)amino, and morpholinyl;    unsubstituted (phenyl)C₁₋₃alkyl; (phenyl)C₁₋₃alkyl wherein the    phenyl and the C₁₋₃alkyl part of the substituent may each be    independently substituted with 1, 2 or 3 substituents independently    selected from the group consisting of halo, C₁₋₃alkyl,    hydroxyC₁₋₃alkyl, C₁₋₃alkyl substituted with one or more    independently selected halo substituents, cyano, hydroxyl, amino,    carboxyl, C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy, C₁₋₃alkyloxy    substituted with one or more independently selected halo    substituents, C₁₋₃alkylcarbonyl, mono- or di(C₁₋₃alkyl)amino,    morpholinyl and (C₃₋₇cycloalkyl)C₁₋₃alkyloxy; unsubstituted    phenyloxy; phenyloxy substituted with 1, 2 or 3 substituents    independently selected from the group consisting of halo, C₁₋₃alkyl,    C₁₋₃alkyl substituted with one or more independently selected halo    substituents, C₁₋₃alkyloxy, and C₁₋₃alkyloxy substituted with one or    more independently selected halo substituents; unsubstituted    phenyloxy(C₁₋₃alkyl)oxy; unsubstituted (phenylC₁₋₃alkyl)oxy;    phenyl(C₁₋₃alkyl)oxy wherein the phenyl part of the substituent is    substituted with 1, 2, or 3 substituents independently selected from    the group consisting of halo, C₁₋₃alkyl, C₁₋₃alkyl substituted with    one or more independently selected halo substituents, C₁₋₃alkyloxy,    and C₁₋₃alkyloxy substituted with one or more independently selected    halo substituents; unsubstituted phenyloxyC₁₋₃alkyl;    (phenyloxy)C₁₋₃alkyl substituted with 1 or 2 substituents    independently selected from the group consisting of halo, C₁₋₃alkyl,    C₁₋₃alkyl substituted with one or more independently selected halo    substituents, C₁₋₃alkyloxy, and C₁₋₃alkyloxy substituted with one or    more independently selected halo substituents; unsubstituted    phenylamino; phenylamino substituted with 1 or 2 independently    selected halo substituents; (phenylC₁₋₃alkyl)amino;    (phenylamino)(C₁₋₃alkyl); (C₃₋₇cycloalkyl)C₁₋₃alkyl;    [phenyl(C₃₋₇cycloalkyl)]C₁₋₃alkyl; Het¹; Het²; Het²oxy;    Het²-methyloxy; Het³; and phenyl with two vicinal substituents which    taken together form a bivalent radical of formula

—N═CH—NH—  (a),

—CH═CH—NH—  (b), or

—O—CH₂—CH₂—NH—  (c);

-   R^(4a) is selected from the group consisting of hydrogen; halogen;    trifluoromethyl; trifluoromethoxy; hydroxyl; C₁₋₃alkyl;    C₁₋₃alkyloxy; hydroxyC₁₋₃alkyl; hydroxyl-C₁₋₃alkyloxy;    fluoroC₁₋₃alkyl; fluoroC₁₋₃alkyloxy; cyano; unsubstituted phenyl;    and phenyl substituted with 1 or 2 substituents independently    selected from the group consisting of halo, C₁₋₃alkyloxy,    hydroxyC₁₋₃alkyl, trifluoromethyl and trifluoromethoxy;-   or CR^(3a)R^(4a) forms a radical of formula (d), (e), (f), (g) or    (h);

-   wherein-   each W^(1d), W^(1e), W^(2e) and W^(1f) is independently selected    from CH and N;-   R^(7d), R^(7e), R^(7f), R^(7g), R^(8d), R^(8e), R^(8f), R^(8g) is    independently selected from hydrogen, methyl and fluoro; or each    CR^(7d)R^(8d), CR^(7e)R^(8e), CR^(7f)R^(8f), CR^(7g)R^(8g) form a    carbonyl group;-   each R^(9d), R^(9e), R^(9f), and R^(9g) is fluoro;-   each q1, q2, q3 or q4 is independently selected from 0, 1 and 2;-   r is 0 or 1;-   s is 0 or 1;-   each R^(3b) and R^(3c) is selected from the group consisting of    C₁₋₃alkyl; C₁₋₃alkyl substituted with one or more independently    selected halo substituents; unsubstituted phenyl; phenyl substituted    with 1, 2 or 3 substituents independently selected from the group    consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, C₁₋₃alkyl    substituted with one or more independently selected halo    substituents, cyano, hydroxyl, amino, carboxyl,    C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy, C₁₋₃alkyloxy substituted with    one or more independently selected halo substituents,    C₁₋₃alkylcarbonyl, mono- and di(C₁₋₃alkyl)amino, and morpholinyl;    unsubstituted (phenyl)C₁₋₃alkyl; (phenyl)C₁₋₃alkyl wherein the    phenyl and the C₁₋₃alkyl part of the substituent may each be    independently substituted with 1, 2 or 3 substituents independently    selected from the group consisting of halo, C₁₋₃alkyl,    hydroxyC₁₋₃alkyl, C₁₋₃alkyl substituted with one or more    independently selected halo substituents, cyano, hydroxyl, amino,    carboxyl, C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy, C₁₋₃alkyloxy    substituted with one or more independently selected halo    substituents, C₁₋₃alkylcarbonyl, mono- or di(C₁₋₃alkyl)amino,    morpholinyl, C₃₋₇cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₃alkyl, and    (C₃₋₇cycloalkyl)-C₁₋₃alkyloxy; unsubstituted (phenyloxy)C₁₋₃alkyl;    (phenyloxy)C₁₋₃alkyl substituted with 1 or 2 substituents    independently selected from the group consisting of halo, C₁₋₃alkyl,    C₁₋₃alkyl substituted with one or more independently selected halo    substituents, C₁₋₃alkyloxy, and C₁₋₃alkyloxy substituted with one or    more independently selected halo substituents;    (phenylamino)(C₁₋₃alkyl); phenyl with two vicinal substituents which    taken together form a bivalent radical of formula (a), (b) or (c) as    previously defined; Het¹; Het²; Het³; unsubstituted C₃₋₇cycloalkyl;    C₃₋₇cycloalkyl substituted with 1 or 2 substituents independently    selected from C₁₋₃alkyl, C₁₋₃alkyl substituted with one or more    independently selected halo substituents, or hydroxyl;    (C₃₋₇cycloalkyl)C₁₋₃alkyl; and [phenyl(C₃₋₇cycloalkyl)]C₁₋₃alkyl;-   R^(3d) and R^(4d) are each independently selected from the group    consisting of hydrogen and C₁₋₃alkyl;-   each R^(5a), R^(5b), R^(5c), R^(5d), R^(6a), R^(6b), R^(6c) and    R^(6d) is independently selected from the group consisting of    hydrogen and C₁₋₃alkyl; or each pair R^(5a)R^(6a), R^(5b)R^(6b),    R^(5c)R^(6c), R^(5d)R^(6d) are substituents on the same carbon atom    and each CR^(5a)R^(6a), CR^(5b)R^(6b), CR^(5c)R^(6c), CR^(5d)R^(6d)    together form a (C═O) or a C₃₋₇cycloalkylidene radical;-   each R^(10a), R^(10b) and R^(10c) is selected from H, C₁₋₃alkyl and    C₁₋₃alkyloxy;-   wherein, in (L-e),-   when t is 1 or 2, R¹¹ is hydrogen and R¹² is selected from a    substituent selected from the group consisting of phenyl, phenyloxy    and phenylamino, each of which may be optionally substituted with 1    or 2 halo substituents; or-   when t is 1 or 3, then CR¹¹R¹² form a radical of formula (i) or    formula (j)

-   wherein-   each R^(13i) and R^(13j) is independently selected from methyl and    trifluoromethyl;-   each R^(14i) or R^(14j) is fluoro;-   each u1 and u2 is independently 0, 1 or 2;-   v1 is selected from the group of 0, 1 and 2;-   v2 is selected from the group of 1 and 2;-   each z1 and z2 is independently selected from the group of 0, 1 and    2;-   each k1 and k2 is independently selected from the group of 0, 1 and    2;-   wherein, in (L-f) w is 1 or 2;-   wherein in (L-g)-   Z is CR¹⁶R¹⁷ and R¹⁵ is hydrogen when each x is 0 and y is 1; or-   Z is CR¹⁶R¹⁷ and R¹⁵ is selected from the group consisting of    hydrogen, methyl and phenyl when each x is 0 and y is 2; or-   Z is NR¹⁶ when each x is 1 and y is 1;-   wherein R¹⁶ and R¹⁷ are each independently selected from the group    consisting of hydrogen; unsubstituted phenyl; and phenyl substituted    with 1, 2 or 3 halo substituents;-   wherein in (L-h),-   Q is O or N—R¹⁸, wherein R¹⁸ is selected from hydrogen and    C₁₋₃alkyl;-   wherein-   each Het¹ is a saturated heterocyclic radical selected from    pyrrolidinyl; piperidinyl; piperazinyl; and morpholinyl; each of    which may be optionally substituted with 1 or 2 substituents    independently selected from the group consisting of C₁₋₆alkyl, halo,    C₁₋₃alkyl substituted with one or more independently selected halo    substituents, unsubstituted phenyl or phenyl substituted with 1, 2    or 3 substituents independently selected from the group consisting    of halo, trifluoromethyl, and trifluoromethoxy; and-   each Het² is an aromatic heterocyclic radical selected from    pyridinyl and pyrimidinyl; each of which is unsubstituted or    substituted with 1 or 2 substituents selected from the group    consisting of halo; C₁₋₃alkyl; C₁₋₃alkyloxy; and C₁₋₃ alkyl    substituted with one or more independently selected halo    substituents;-   each Het³ is a heterocyclic radical selected from 1,3-thiazolyl    optionally substituted with C₁₋₃alkyl; unsubstituted benzofuranyl;    unsubstituted 3,4-dihydro-2H-chromenyl; and unsubstituted    1H-indolyl;-   each halo is selected from the group consisting of fluoro, chloro,    bromo and iodo;-   and the pharmaceutically acceptable salts and the solvates thereof.

The names of the compounds of the present invention were generatedaccording to the nomenclature rules agreed upon by the ChemicalAbstracts Service (CAS) using Advanced Chemical Development, Inc.,software (ACD/Name product version 10.01; Build 15494, 1 Dec. 2006). Incase of tautomeric forms, the name of the depicted tautomeric form ofthe structure was generated. However it should be clear that the othernon-depicted tautomeric form is also included within the scope of thepresent invention.

Definitions

The notation “C₁₋₃alkyl” or “C₁₋₆alkyl” as used herein alone or as partof another group, defines a saturated, straight or branched, hydrocarbonradical having, unless otherwise stated, from 1 to 3 or 1 to 6 carbonatoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, butyl,1-methyl-propyl, 2-methyl-1-propyl, 1,1-dimethylethyl, 3-methyl-1-butyl,1-pentyl, 1-hexyl and the like.

The notation “C₃₋₇cycloalkyl” as used herein alone or as part of anothergroup, defines a saturated, cyclic hydrocarbon radical having from 3 to7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl.

The notation “C₃₋₇cycloalkylC₁₋₃alkyl” as used herein alone or as partof another group, defines a saturated, cyclic hydrocarbon radical havingfrom 3 to 7 carbon atoms bound through a saturated, straight hydrocarbonradical having from 1 to 3 carbon atoms, such as cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl and the like.

The notation “halogen” or “halo” as used herein alone or as part ofanother group, refers to fluoro, chloro, bromo or iodo, with fluoro orchloro being preferred.

The notation “C₁₋₃alkyl substituted with one or more independentlyselected halo substituents” as used herein alone or as part of anothergroup, defines an alkyl group as defined above, substituted with 1, 2, 3or more halogen atoms, such as fluoromethyl; difluoromethyl;trifluoromethyl; 2,2,2-trifluoro ethyl; 1,1-difluoroethyl;3,3,3-trifluoropropyl. Preferred examples of these groups aretrifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and1,1-difluoroethyl.

The notation “mono-, di- or tri-haloC₁₋₃alkyl” as used herein alone oras part of another group, defines an alkyl group as defined above,substituted with 1, 2 or 3 halogen atoms, such as fluoromethyl;difluoromethyl; trifluoromethyl; 2,2,2-trifluoroethyl;1,1-difluoroethyl; 3,3,3-trifluoropropyl. Preferred examples of thesegroups are trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyland 1,1-difluoroethyl.

The notation “C₃₋₇cycloalkylidene” as used herein, refers to a bivalentC₃₋₇cycloalkane group, by removal of 2 hydrogen atoms from the samecarbon atom, such as for example, cyclopropylidene, cyclobutylidene,cyclopentylidene, cyclohexylidene and the like.

Whenever the term “substituted” is used in the present invention, it ismeant, unless otherwise is indicated or is clear from the context, toindicate that one or more hydrogens, preferably from 1 to 3 hydrogens,more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen, onthe atom or radical indicated in the expression using “substituted” arereplaced with a selection from the indicated group, provided that thenormal valency is not exceeded, and that the substitution results in achemically stable compound, i.e. a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

The substituents covered by the terms Het¹, Het² or Het³ may be attachedto the remainder of the molecule of formula (I) through any ring carbonor heteroatom as appropriate, if not otherwise specified. Thus, forexample, when the Het¹ substituent is morpholinyl, it may be2-morpholinyl, 3-morpholinyl or 4-morpholinyl; when the Het² substituentis pyridinyl, it may be 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.Preferred Het¹ substituents are those linked to the rest of the moleculethrough the nitrogen atom.

It will be appreciated that some of the compounds of formula (I) andtheir pharmaceutically acceptable addition salts and solvates thereofmay contain one or more centres of chirality and exist as stereoisomericforms.

The term “stereoisomeric forms” as used hereinbefore defines all thepossible isomeric forms that the compounds of Formula (I) may possess.Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereochemically isomericforms, said mixtures containing all diastereomers and enantiomers of thebasic molecular structure. More in particular, stereogenic centres mayhave the R- or S-configuration; substituents on bivalent cyclic(partially) saturated radicals may have either the cis- ortrans-configuration. Compounds encompassing double bonds can have an E-or Z-stereochemistry at said double bond. Stereoisomeric forms of thecompounds of Formula (I) are embraced within the scope of thisinvention.

When a specific stereoisomeric form is indicated, this means that saidform is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other isomers. Thus, when a compound of formula (I)is for instance specified as (R), this means that the compound issubstantially free of the (S) isomer.

Following CAS nomenclature conventions, when two stereogenic centres ofknown absolute configuration are present in a compound, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral centre, the reference centre. Theconfiguration of the second stereogenic centre is indicated usingrelative descriptors [R*,R*] or [R*,S*], where R* is always specified asthe reference centre and [R*,R*] indicates centres with the samechirality and [R*,S*] indicates centres of unlike chirality. Forexample, if the lowest-numbered chiral centre in the compound has anS-configuration and the second centre is R, the stereo descriptor wouldbe specified as S—[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system (hydrogen atom in compounds according to Formula (I))relative to the position of the highest priority substituent on thereference atom is denominated “α” if it is on the same side of the meanplane determined by the ring system, or “β”, if it is on the other sideof the mean plane determined by the ring system.

Preferred features of the compounds of this invention are now set forth.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from the group consisting of 0 and 1;-   m is selected from the group consisting of 0 and 1;-   R is selected from methyl or trifluoromethyl;-   R¹ is selected from the group consisting of C₁₋₆alkyl;    (C₁₋₃alkyloxy)C₁₋₃alkyl; [(C₁₋₃alkyloxy)C₁₋₃alkyloxy]C₁₋₃alkyl;    C₁₋₃alkyl substituted with one or more independently selected halo    substituents; unsubstituted phenyl; unsubstituted benzyl; benzyl    substituted with 1, 2 or 3 substituents independently selected from    the group consisting of halo, C₁₋₃alkyl, C₁₋₃alkyloxy,    C₁₋₃alkyloxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl, cyano, hydroxyl,    morpholinyl, trifluoromethyl and trifluoromethoxy;    (benzyloxy)C₁₋₃alkyl; unsubstituted C₃₋₇cycloalkyl; C₃₋₇cycloalkyl    substituted with C₁₋₃alkyl substituted with one or more    independently selected halo substituents; (C₃₋₇cycloalkyl)C₁₋₃alkyl;    [(C₃₋₇cycloalkyl)C₁₋₃alkyloxy]C₁₋₃alkyl;    (C₃₋₇cycloalkyl)C₁₋₃alkyloxy; Het¹; Het¹C₁₋₃alkyl; Het²; and    Het²C₁₋₃alkyl;-   R² is selected from the group consisting of cyano; halo; C₁₋₃alkyl    substituted with one or more independently selected halo    substituents; C₁₋₃alkyloxy substituted with one or more    independently selected halo substituents; C₁₋₃alkyl; C₃₋₇cycloalkyl;    and (C₃₋₇cycloalkyl)C₁₋₃alkyl;

-   is selected from the group consisting of (L-a), (L-b), (L-c), (L-d),    (L-e), (L-0, (L-g) and (L-h); wherein-   R^(3a) is selected from the group consisting of C₁₋₃alkyl; C₁₋₃alkyl    substituted with one or more independently selected halo    substituents; unsubstituted C₃₋₇cycloalkyl; C₃₋₇cycloalkyl    substituted with 1 or 2 substituents independently selected from    C₁₋₃alkyl, C₁₋₃alkyl substituted with one or more independently    selected halo substituents or hydroxyl; unsubstituted phenyl; phenyl    substituted with 1, 2 or 3 substituents independently selected from    the group consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, C₁₋₃alkyl    substituted with one or more independently selected halo    substituents, cyano, hydroxyl, C₁₋₃alkyloxy-C₁₋₃alkyl, C₁₋₃alkyloxy,    and morpholinyl; unsubstituted (phenyl)C₁₋₃alkyl; (phenyl)C₁₋₃alkyl    wherein the phenyl and the C₁₋₃alkyl part of the substituent may    each be independently substituted with 1, 2 or 3 substituents    independently selected from the group consisting of halo, C₁₋₃alkyl,    hydroxyC₁₋₃alkyl, C₁₋₃alkyl substituted with one or more    independently selected halo substituents, C₁₋₃alkyloxy, and    (C₃₋₇cycloalkyl)-C₁₋₃alkyloxy; unsubstituted phenyloxy; phenyloxy    substituted with 1, 2 or 3 substituents independently selected from    the group consisting of halo, C₁₋₃alkyl, C₁₋₃alkyl substituted with    one or more independently selected halo substituents, and    C₁₋₃alkyloxy; unsubstituted (phenylC₁₋₃alkyl)oxy;    phenyl(C₁₋₃alkyl)oxy wherein the phenyl part of the substituent is    substituted with 1, 2, or 3 substituents independently selected from    the group consisting of halo, C₁₋₃alkyl, C₁₋₃alkyl substituted with    one or more independently selected halo substituents, and    C₁₋₃alkyloxy; (phenyloxy)C₁₋₃alkyl substituted with 1 or 2 halo    substituents; unsubstituted phenylamino; phenylamino substituted    with 1 or 2 halo substituents; (phenylC₁₋₃alkyl)amino;    (phenylamino)(C₁₋₃alkyl); Het¹; Het²; Het²oxy; Het²-methyloxy; and    Het³;-   R^(4a) is selected from the group consisting of hydrogen; halogen;    trifluoromethyl; trifluoromethoxy; hydroxyl; C₁₋₃alkyl;    C₁₋₃alkyloxy; and unsubstituted phenyl;-   or CR^(3a)R^(4a) forms a radical of formula (d), (e), (f), (g) or    (h); wherein-   each W^(1d), W^(1e), W^(2e) and W^(1f) is independently selected    from CH and N;-   each R^(7d), R^(7e), R^(7f), R^(7g), R^(8d), R^(8e), R^(8f), R^(8g)    is independently selected from hydrogen, methyl and fluoro; or each    CR^(7d)R^(8d), CR^(7g)R^(8g) form a carbonyl group;-   each R^(9d), R^(9e), R^(9f), and R^(9g) is fluoro;-   each q1, q2, q3 or q4 is independently selected from 0, 1 and 2;-   r is 0 or 1;-   s is 0 or 1;-   each R^(3b) and R^(3c) is selected from the group consisting of    C₁₋₃alkyl; C₁₋₃alkyl substituted with one or more independently    selected halo substituents; unsubstituted phenyl; phenyl substituted    with 1, 2 or 3 substituents independently selected from the group    consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, C₁₋₃alkyl    substituted with one or more independently selected halo    substituents, C₁₋₃alkyloxyC₁₋₃alkyl, and C₁₋₃alkyloxy; unsubstituted    (phenyl)C₁₋₃alkyl; (phenyl)C₁₋₃alkyl wherein the phenyl and the    C₁₋₃alkyl part of the substituent may each be independently    substituted with 1, 2 or 3 substituents independently selected from    the group consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, C₁₋₃alkyl    substituted with one or more independently selected halo    substituents, C₃₋₇cycloalkyl, (C₃₋₇cycloalkyl)-C₁₋₃alkyl, and    (C₃₋₇cycloalkyl)-C₁₋₃alkyloxy; (phenyloxy)C₁₋₃alkyl substituted with    1 or 2 substituents independently selected from the group consisting    of halo, C₁₋₃alkyl, and C₁₋₃alkyl substituted with one or more    independently selected halo substituents; (phenyl amino)(C₁₋₃alkyl);    Het¹; Het²; Het³; unsubstituted C₃₋₇cycloalkyl; C₃₋₇cycloalkyl    substituted with 1 or 2 substituents independently selected from    C₁₋₃alkyl, C₁₋₃alkyl substituted with one or more independently    selected halo substituents, and hydroxyl; and    [phenyl(C₃₋₇cycloalkyl)]C₁₋₃alkyl;-   R^(3d) and R^(4d) are each independently selected from the group    consisting of hydrogen and C₁₋₃alkyl;-   each R^(5a), R^(5b), R^(5c), R^(5d), R^(6a), R^(6b), R^(6c) and    R^(6d) is independently selected from the group consisting of    hydrogen and C₁₋₃alkyl; or each pair R^(5a)R^(6a), R^(5b)R^(6b),    R^(5c)R^(6c), R^(5d)R^(6d) are substituents on the same carbon atom    and each CR^(5a)R^(6a), CR^(5b)R^(6b), CR^(5c)R^(6c), CR^(5d)R^(6d)    together form a (C═O) or a C₃₋₇cycloalkylidene radical;-   each R^(10a), R^(10b) and R^(10c) is selected from H, and C₁₋₃alkyl;-   wherein, in (L-e),-   when t is 1 or 2, R¹¹ is hydrogen and R¹² is selected from a    substituent selected from the group consisting of phenyl, phenyloxy    and phenylamino, each of which may be optionally substituted with 1    or 2 halo substituents; or-   when t is 1 or 3, then CR¹¹R¹² form a radical of formula (i);    wherein-   R^(13i) is methyl;-   R^(14i) is fluoro;-   u1 is 0 or 1;-   v1 is 0, 1 or 2;-   z1 is selected from the group of 0, 1 and 2;-   k1 is 0 or 1;-   wherein, in (L-f) w is 1 or 2;-   wherein in (L-g)-   Z is CR¹⁶R¹⁷ and R¹⁵ is hydrogen when each x is 0 and y is 1; or-   Z is CR¹⁶R¹⁷ and R¹⁵ is selected from the group consisting of    hydrogen, methyl and phenyl when each x is 0 and y is 2; or-   Z is NR¹⁶ when each x is 1 and y is 1;-   wherein R¹⁶ and R¹⁷ are each independently selected from the group    consisting of hydrogen; unsubstituted phenyl; and phenyl substituted    with 1, 2 or 3 halo substituents;-   wherein in (L-h),-   Q is O or N—R¹⁸, wherein R¹⁸ is selected from hydrogen and    C₁₋₃alkyl;-   wherein-   each Het¹ is a saturated heterocyclic radical selected from    pyrrolidinyl; piperidinyl; piperazinyl; and morpholinyl; each of    which may be optionally substituted with 1 or 2 substituents    independently selected from the group consisting of C₁₋₆alkyl, halo,    C₁₋₃alkyl substituted with one or more independently selected halo    substituents, unsubstituted phenyl or phenyl substituted with 1, 2    or 3 substituents independently selected from the group consisting    of halo, trifluoromethyl, and trifluoromethoxy;-   each Het² is an aromatic heterocyclic radical selected from    pyridinyl and pyrimidinyl; each of which is unsubstituted or    substituted with 1 or 2 substituents selected from the group    consisting of halo; C₁₋₃alkyl; C₁₋₃alkyloxy; and C₁₋₃alkyl    substituted with one or more independently selected halo    substituents;-   each Het³ is a heterocyclic radical selected from 1,3-thiazolyl    optionally substituted with C₁₋₃alkyl; unsubstituted benzofuranyl;    unsubstituted 3,4-dihydro-2H-chromenyl; and unsubstituted    1H-indolyl;-   each halo is selected from the group consisting of fluoro, chloro,    and bromo;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 and 1;-   m is selected from 0 and 1;-   R is methyl;-   R¹ is selected from the group consisting of C₁₋₆alkyl;    (C₁₋₃alkyloxy)C₁₋₃alkyl; [(C₁₋₃alkyloxy)-C₁₋₃alkyloxy]C₁₋₃alkyl;    C₁₋₃alkyl substituted with one or more halo substituents;    unsubstituted phenyl; (benzyloxy)C₁₋₃alkyl; unsubstituted    C₃₋₇cycloalkyl; C₃₋₇cycloalkyl substituted with C₁₋₃alkyl    substituted with one or more halo substituents;    (C₃₋₇cycloalkyl)C₁₋₃alkyl; [(C₃₋₇cycloalkyl)C₁₋₃alkyloxy]-C₁₋₃alkyl;    (C₃₋₇cycloalkyl)C₁₋₃alkyloxy; Het¹C₁₋₃alkyl; Het²; and    Het²C₁₋₃alkyl;-   R² is selected from the group consisting of cyano; halo; C₁₋₃alkyl    substituted with one or more halo substituents; C₁₋₃alkyl; and    C₃₋₇cycloalkyl;

-   is an N-containing heterocycle selected from the group consisting of    (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L-h); wherein-   R^(3a) is selected from the group consisting of C₁₋₃alkyl    substituted with one or more halo substituents; unsubstituted    phenyl; phenyl substituted with 1, 2 or 3 substituents independently    selected from the group consisting of halo, hydroxyC₁₋₃alkyl,    C₁₋₃alkyl substituted with one or more halo substituents, hydroxyl,    and C₁₋₃alkyloxy; phenyloxy substituted with 1 or 2 independently    selected halo substituents; phenyl(C₁₋₃alkyl)oxy wherein the phenyl    part of the substituent is substituted with 1, 2, or 3 independently    selected halo substituents; (phenyloxy)C₁₋₃alkyl wherein the phenyl    part of the substituent is substituted with 1 or 2 halo    substituents; unsubstituted phenylamino; phenylamino substituted    with 1 or 2 halo substituents; (phenylC₁₋₃alkyl)amino; Het¹; Het²;    Het²oxy; Het²-methyloxy; and Het³;-   R^(4a) is selected from the group consisting of hydrogen; halogen;    trifluoromethyl; C₁₋₃alkyl; C₁₋₃alkyloxy; and unsubstituted phenyl;-   or CR^(3a)R^(4a) forms a radical of formula (d), (e), (f), (g) or    (h); wherein-   each W^(1d), W^(1e), W^(2e) and W^(1f) is independently selected    from CH and N;-   each R^(7d), R^(7e), R^(7f), R^(7g), R^(8d), R^(8e), R^(8f), R^(8g)    is independently selected from hydrogen, methyl and fluoro; or each    CR^(7d)R^(8d), CR^(7g)R^(8g) form a carbonyl group;-   each R^(9d), R^(9e), R^(9f), and R^(9g) is fluoro;-   each q1, q2, q3 or q4 is independently selected from 0, 1 and 2;-   r is 0 or 1;-   s is 0 or 1;-   each R^(3b) and R^(3c) is selected from the group consisting of    C₁₋₃alkyl substituted with one or more halo substituents;    unsubstituted phenyl; phenyl substituted with 1, 2 or 3 substituents    independently selected from the group consisting of halo,    C₁₋₃alkyloxy and C₁₋₃alkyl substituted with one or more halo    substituents; unsubstituted (phenyl)C₁₋₃alkyl; (phenyl)C₁₋₃alkyl    wherein the phenyl and the C₁₋₃alkyl parts of the substituent may    each be independently substituted with 1, 2 or 3 substituents    independently selected from the group consisting of halo, C₁₋₃alkyl,    C₁₋₃alkyl substituted with one or more halo substituents, and    (C₃₋₇cycloalkyl)-C₁₋₃alkyloxy; Het²; Het³; C₃₋₇cycloalkyl    substituted with 1 or 2 substituents independently selected from the    group consisting of C₁₋₃ alkyl, C₁₋₃alkyl substituted with one or    more halo substituents, and hydroxyl; and    [phenyl(C₃₋₇cycloalkyl)]C₁₋₃alkyl;-   each R^(3d) and R^(4d) is independently selected from hydrogen and    C₁₋₃alkyl;-   each R^(5a), R^(5b), R^(5c), R^(5d), R^(6a), R^(6b), R^(6c) and    R^(6d) is independently selected from the group consisting of    hydrogen and C₁₋₃alkyl; or CR^(5b)R^(6b) together form a (C═O) or a    C₃₋₇cycloalkylidene radical;-   each R^(10a), R^(10b) and R^(10c) is H;-   wherein, in (L-e),-   when t is 1 or 2, R¹¹ is hydrogen and R¹² is selected from a    substituent selected from the group consisting of phenyl, phenyloxy    and phenylamino, each of which may be optionally substituted with 1    or 2 halo substituents; or-   when t is 1, then CR¹¹R¹² form a radical of formula (i); wherein-   R^(14i) is fluoro;-   u1 is 0 or 1;-   v1 is 2;-   z1 is selected from the group of 1 and 2;-   k1 is 0; or-   when t is 3, then CR¹¹R¹² form a radical of formula (i); wherein-   R^(14i) is fluoro;-   u1 is 0 or 1;-   v1 is 0;-   z1 is selected from the group of 1 and 2;-   k1 is 0;-   wherein, in (L-f) w is 1 or 2;-   wherein in (L-g)-   Z is CR¹⁶R¹⁷ and R¹⁵ is hydrogen when each x is 0 and y is 1; or-   Z is CR¹⁶R¹⁷ and R¹⁵ is phenyl when each x is 0 and y is 2; or-   Z is NR¹⁶ when each x is 1 and y is 1;-   wherein R¹⁶ and R¹⁷ are each independently selected from the group    consisting of hydrogen; unsubstituted phenyl; and phenyl substituted    with 1, 2 or 3 halo substituents;-   wherein in (L-h), Q is 0;-   each Het¹ is a saturated heterocyclic radical selected from    pyrrolidinyl; piperidinyl; piperazinyl; and morpholinyl; each of    which is unsubstituted or substituted with 1 or 2 substituents    independently selected from the group consisting of fluoro,    C₁₋₃alkyl substituted with one or more halo substituents, and    unsubstituted phenyl; and-   each Het² is an aromatic heterocyclic radical selected from    pyridinyl and pyrimidinyl; each of which is unsubstituted or    substituted with 1 or 2 substituents independently selected from the    group consisting of halo; C₁₋₃alkyl; and C₁₋₃alkyloxy;-   each Het³ is a heterocyclic radical selected from 1,3-thiazolyl    optionally substituted with C₁₋₃alkyl; unsubstituted benzofuranyl;    unsubstituted 3,4-dihydro-2H-chromenyl; and unsubstituted    1H-indolyl;-   each halo is selected from the group consisting of fluoro, chloro,    and bromo;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 and 1;-   m is selected from 0 and 1;-   R is methyl;-   R¹ is selected from the group consisting of C₁₋₆alkyl;    (C₁₋₃alkyloxy)C₁₋₃alkyl; [(C₁₋₃alkyloxy)-C₁₋₃alkyloxy]C₁₋₃alkyl;    C₁₋₃alkyl substituted with one or more halo substituents;    unsubstituted phenyl; (benzyloxy)C₁₋₃alkyl; unsubstituted    C₃₋₇cycloalkyl; C₃₋₇cycloalkyl substituted with trifluoromethyl;    (C₃₋₇cycloalkyl)C₁₋₃alkyl; [(C₃₋₇cycloalkyl)C₁₋₃alkyloxy]-C₁₋₃alkyl;    (C₃₋₇cycloalkyl)C₁₋₃alkyloxy; pyrrolidinylmethyl; morpholinylmethyl;    piperidinylmethyl substituted with phenyl; piperidinylmethyl    substituted with trifluoromethyl; pyridinyl; and pyridinylmethyl;-   R² is selected from the group consisting of cyano; halo; C₁₋₃alkyl    substituted with one or more halo substituents; C₁₋₃alkyl; and    cyclopropyl;

-   is an N-containing heterocycle selected from the group consisting of    (L-a), (L-b), (L-c), (L-e), (L-f), (L-g) and (L-h); wherein-   R^(3a) is selected from the group consisting of trifluoromethyl;    phenyl; phenyl substituted with 1, 2 or 3 substituents independently    selected from the group consisting of halo, 2-hydroxyprop-2-yl,    trifluoromethyl, hydroxyl, methoxy, and ethoxy; phenyloxy    substituted with 1 or 2 independently selected halo substituents;    phenyl(C₁₋₃alkyl)oxy wherein the phenyl part of the substituent is    substituted with 1, 2, or 3 independently selected halo    substituents; (phenyloxy)C₁₋₃alkyl wherein the phenyl part is    substituted with 1 or 2 halo substituents; phenylamino; phenylamino    substituted with 1 or 2 halo substituents; benzylamino; morpholinyl;    pyrrolidinyl substituted with 1 or 2 halo substituents; piperidinyl    substituted with 1 or 2 halo substituents; pyridinyl; pyridinyl    substituted with 1 or 2 substituents independently selected from    halo, methyl and methoxy; pyrimidinyl; pyrimidinyl substituted with    1 or 2 substituents independently selected from halo and methoxy;    pyridinylmethyloxy; and 1H-indol-1-yl;-   R^(4a) is selected from the group consisting of hydrogen; halo;    trifluoromethyl; C₁₋₃alkyl; methoxy; and phenyl;-   or CR^(3a)R^(4a) forms a radical of formula (d), (e), (f), (g) or    (h); wherein-   each W^(1d), W^(1e), W^(2e) is independently selected from CH and N;-   W^(1f) is CH;-   R^(7d) and R^(8d) are selected from hydrogen, methyl and fluoro; or    CR^(7d)R^(8d) forms a carbonyl group;-   R^(7e), R^(7f), R^(8e) and R^(8f) are hydrogen;-   R^(7g) and R^(8g) are hydrogen; or CR^(7g)R^(8g) forms a carbonyl    group;-   each R^(9d) and R^(9g) is fluoro;-   q1 is selected from 0 or 1;-   each q2 and q3 is 0;-   q4 is selected from 1 and 2;-   r is 0 or 1;-   s is 0 or 1;-   R^(3b) is selected from the group consisting of    3,3,3-trifluoropropyl; phenyl; phenyl substituted with 1, or 2    substituents independently selected from the group consisting of    halo, methoxy, ethoxy and trifluoromethyl; benzyl; (phenyl)methyl    wherein the phenyl part of the substituent may be substituted with 1    or 2 substituents independently selected from the group consisting    of halo, trifluoromethyl and cyclopropylmethyloxy, and the methyl    part of the substituent may be optionally substituted with methyl or    trifluoromethyl; phenylethyl; cyclohexyl substituted with 1 or 2    substituents independently selected from the group consisting of    methyl, trifluoromethyl, and hydroxyl; (2-phenylcyclopropyl)methyl;    pyridinyl; pyridinyl substituted with 1 or 2 substituents    independently selected from the group consisting of halo; and    methoxy; pyrimidinyl; pyrimidinyl substituted with 1 or 2    substituents independently selected from halo, methyl and methoxy;    1,3-thiazolyl substituted with methyl; unsubstituted benzofuranyl;    and unsubstituted 3,4-dihydro-2H-chromenyl;-   R^(3c) is phenyl substituted with 1 or 2 halo substituents;-   R^(5a) and R^(6a) are independently selected from the group    consisting of hydrogen and methyl;-   R^(5b) and R^(6b) are independently selected from the group    consisting of hydrogen and methyl; or CR^(5b)R^(6b) together forms a    carbonyl or a cyclopropylidene radical;-   R^(5c) and R^(6c) are hydrogen;-   each R^(10a), R^(10b) and R^(10c) is H;-   wherein, in (L-e),-   when t is 1 or 2, R¹¹ is hydrogen and R¹² is selected from a    substituent selected from the group consisting of phenyl; phenyloxy;    and phenylamino substituted with 1 or 2 halo substituents; or-   when t is 1, then CR¹¹R¹² form a radical of formula (i); wherein-   R^(14i) is fluoro;-   u1 is 0, 1 or 2;-   v1 is 2;-   z1 is selected from 1 and 2;-   k1 is 0; or-   when t is 3, then CR¹¹R¹² form a radical of formula (i); wherein-   R^(14i) is fluoro;-   u1 is 0 or 1;-   v1 is 0;-   z1 is selected from 1 and 2;-   k1 is 0;-   wherein, in (L-f) w is 1 or 2;-   wherein in (L-g)-   Z is CR¹⁶R¹⁷ and R¹⁵ is hydrogen when each x is 0 and y is 1; or-   Z is CR¹⁶R¹⁷ and R¹⁵ is phenyl when each x is 0 and y is 2; or-   Z is NR¹⁶ when each x is 1 and y is 1;-   wherein R¹⁶ and R¹⁷ are each independently selected from the group    consisting of hydrogen; unsubstituted phenyl; and phenyl substituted    with 1 or 2 halo substituents;-   wherein in (L-h), Q is 0;-   each halo is selected from the group consisting of fluoro, chloro    and bromo;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 and 1;-   m is 0 or 1;-   R is methyl;-   R¹ is selected from the group consisting of C₁₋₆alkyl; C₁₋₃alkyl    substituted with one or more independently selected halo    substituents; (C₁₋₃alkyloxy)C₁₋₃alkyl; and    (C₃₋₇cycloalkyl)C₁₋₃alkyl;-   R² is selected from halo; cyano; C₁₋₃alkyl; and C₁₋₃alkyl    substituted with one or more independently selected halo    substituents;

-   is selected from (L-a); (L-b); and (L-g) wherein-   R^(3a) is selected from the group consisting of unsubstituted    phenyl; phenyl substituted with 1 or 2 independently selected halo    substituents; pyridinyl; pyridinyl substituted with 1 or 2 halo    substituents; pyrimidinyl; and pyrimidinyl substituted with 1 or 2    independently selected halo substituents;-   R^(4a) is selected from hydrogen; halo; C₁₋₃alkyl; and    trifluoromethyl;-   or CR^(3a)R^(4a) forms a radical of formula (d); wherein-   W^(1d) is CH;-   R^(7d) and R^(8d) are both methyl;-   R^(9d) is fluoro;-   q1 is 1;-   R^(3b) is selected from unsubstituted phenyl; phenyl substituted    with 1 or 2 halo substituents; unsubstituted pyridinyl; and    pyridinyl substituted with 1 or 2 halo substituents;-   R^(5a), R^(5b), R^(6a) and R^(6b) are hydrogen; and-   R^(10a) and R^(10b) are hydrogen;-   each x is 0 and y is 1;-   R¹⁵ is hydrogen;-   Z is CR¹⁶R¹⁷; wherein-   R¹⁶ and R¹⁷ are each independently selected from hydrogen;    unsubstituted phenyl; and phenyl substituted with 1 or 2 halo    substituents;-   halo is fluoro or chloro;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 or 1;-   m is 0 or 1;-   R is methyl;-   R¹ is selected from the group consisting of C₁₋₆alkyl; C₁₋₃alkyl    substituted with one or more independently selected halo    substituents; and (C₃₋₇cycloalkyl)C₁₋₃alkyl;-   R² is selected from halo, C₁₋₃alkyl, and C₁₋₃alkyl substituted with    one or more independently selected halo substituents;

-   is selected from (L-a) and (L-b); wherein-   R^(3a) is selected from the group consisting of unsubstituted    phenyl; phenyl substituted with 1 or 2 independently selected halo    substituents; pyridinyl; and pyrimidinyl;-   R^(4a) is selected from hydrogen; halo and C₁₋₃alkyl;-   or CR^(3a)R^(4a) forms a radical of formula (d); wherein-   W^(1d) is CH;-   R^(7d) and R^(8d) are both methyl;-   R^(9d) is fluoro;-   q1 is 1;-   R^(3b) is phenyl substituted with 1 or 2 halo substituents;-   R^(5a), R^(5b), R^(6a) and R^(6b) are hydrogen; and-   R^(10a) and R^(10b) are hydrogen;-   halo is fluoro or chloro;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 and 1;-   m is 0 or 1;-   R is methyl;-   R¹ is selected from the group consisting of ethyl; propyl; butyl;    CH₂CF₃; CH₂CH₂CF₃; and cyclopropylmethyl;-   R² is selected from chloro, methyl, and CF₃;

-   is selected from (L-a1) and (L-b1);

-   wherein-   R^(3a) is selected from the group consisting of unsubstituted    phenyl; 2-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl;    2,6-difluorophenyl; 2-pyridinyl; 2-pyrimidinyl;-   R^(4a) is selected from hydrogen; fluoro and methyl;-   or CR^(3a)R^(4a) forms a radical of formula (d4);

-   R^(3b) is 2,4-difluorophenyl;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 and 1;-   m is 0;-   R¹ is selected from the group consisting of C₁₋₃alkyl substituted    with one or more independently selected halo substituents; and    (C₃₋₇cycloalkyl)C₁₋₃alkyl;-   R² is selected from halo and C₁₋₃alkyl substituted with one or more    independently selected halo substituents;

-   is selected from (L-a) and (L-b); wherein-   R^(3a) is selected from the group consisting of unsubstituted    phenyl; and phenyl substituted with 1 or 2 independently selected    halo substituents;-   R^(4a) is hydrogen, fluoro or methyl;-   or CR^(3a)R^(4a) forms a radical of formula (d); wherein-   W^(1d) is CH;-   R^(7d) and R^(8d) are both methyl;-   R^(9d) is fluoro;-   q1 is 1;-   R^(3b) is phenyl substituted with 1 or 2 halo substituents;-   R^(5a), R^(5b), R^(6a) and R^(6b) are hydrogen; and-   R^(10a) and R^(10b) are hydrogen;-   halo is fluoro or chloro;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 and 1;-   m is 0;-   R¹ is selected from the group consisting of C₁₋₃alkyl substituted    with one or more fluoro substituents; and (C₃₋₇cycloalkyl)C₁₋₃alkyl;-   R² is selected from chloro and C₁₋₃alkyl substituted with one or    more fluoro substituents:

-   is selected from (L-a1) and (L-b1);

-   wherein-   R^(3a) is selected from the group consisting of unsubstituted    phenyl; and phenyl substituted with fluoro;-   R^(4a) is hydrogen, fluoro or methyl;-   or CR^(3a)R^(4a) forms a radical of formula (d4);

-   R^(3b) is phenyl substituted with 2 fluoro substituents;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 or 1;-   m is 0;-   R¹ is selected from 2,2,2-trifluoroethyl and cyclopropylmethyl;-   R² is selected from chloro and trifluoromethyl;

-   is selected from (L-a1) and (L-b1);

-   wherein-   R^(3a) is selected from the group consisting of unsubstituted    phenyl; and 4-fluorophenyl;-   R^(4a) is hydrogen, fluoro or methyl;-   or CR^(3a)R^(4a) forms a radical of formula (d4);

-   R^(3b) is 2,4-difluorophenyl;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I′)

and the stereochemically isomeric forms thereof, wherein

is an N-containing heterocycle selected from the group consisting of

R¹ is selected from hydrogen; C₁₋₆alkyl; (C₁₋₃alkyloxy)C₁₋₃alkyl;[(C₁₋₃alkyloxy)-C₁₋₃alkyloxy]C₁₋₃alkyl; mono-, di- or tri-haloC₁₋₃alkyl;unsubstituted benzyl; benzyl substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halo, C₁₋₃alkyl,C₁₋₃alkyloxy, C₁₋₃alkyloxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl, cyano, hydroxyl,amino, C(═O)R′, C(═O)OR′, C(═O)NR′R″, mono- or di(C₁₋₃alkyl)amino,morpholinyl, (C₃₋₇cycloalkyl)C₁₋₃alkyloxy, trifluoromethyl andtrifluoromethoxy, wherein R′ and R″ are independently selected fromhydrogen and C₁₋₆alkyl; (benzyloxy)C₁₋₃alkyl; unsubstitutedC₃₋₇cycloalkyl; C₃₋₇cycloalkyl substituted with trihaloC₁₋₃alkyl;(C₃₋₇cycloalkyl)C₁₋₃alkyl; 4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methyl; Het¹; Het¹C₁₋₃alkyl; Het² and Het²C₁₋₃alkyl;R² is selected from cyano; halo; mono-, di- or tri-haloC₁₋₃alkyl; mono-,di- and tri-haloC₁₋₃alkyloxy; C₁₋₃alkyl; C₃₋₇cycloalkyl; and(C₃₋₇cycloalkyl)C₁₋₃alkyl;R^(3a) and R^(3b) are each selected from unsubstituted phenyl; phenylsubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, mono-, di- andtri-haloC₁₋₃alkyl, cyano, hydroxyl, amino, carboxyl,C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy, mono-, di- or tri-haloC₁₋₃alkyloxy,C₁₋₃alkylcarbonyl, mono- and di(C₁₋₃alkyl)amino, and morpholinyl;unsubstituted benzyl; benzyl substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halo, C₁₋₃alkyl,hydroxyC₁₋₃alkyl, mono-, di- or tri-haloC₁₋₃alkyl, cyano, hydroxyl,amino, carboxyl, C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy, mono-, di- andtri-haloC₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, mono- or di(C₁₋₃alkyl)amino,morpholinyl and (C₃₋₇cycloalkyl)C₁₋₃alkyloxy; phenyl with two vicinalsubstituents which taken together form a bivalent radical of formula

—N═CH—NH—  (a),

—CH═CH—NH—  (b), or

—O—CH₂—CH₂—NH—  (c);

morpholinyl; pyridinyl; pyrimidinyl; pyridinyloxy substituted with 1 or2 C₁₋₃alkyl groups; unsubstituted C₃₋₇cycloalkyl and C₃₋₇cycloalkylsubstituted with 1 or 2 substituents independently selected fromC₁₋₃alkyl, trihaloC₁₋₃alkyl and hydroxyl;R^(4a) is selected from hydrogen; halogen; trifluoromethyl;trifluoromethoxy; hydroxyl; C₁₋₃alkyl; C₁₋₃alkyloxy; hydroxyC₁₋₃alkyl;hydroxylC₁₋₃alkyloxy; fluoroC₁₋₃alkyl; fluoroC₁₋₃alkyloxy; cyano;unsubstituted phenyl; and phenyl substituted with 1 or 2 substituentsindependently selected from the group consisting of halo, C₁₋₃alkyloxy,hydroxyC₁₋₃alkyl, trifluoromethyl and trifluoromethoxy;orR^(3a)—C—R^(4a) together represent a radical of formula (d′) or (e′) or(f′) or (g′)

whereinW^(1d), W^(1e) and W^(1f) are each selected from CH or N;R^(6d), R^(7e), R^(7f), R^(8d), and R^(8f) are each independentlyselected from hydrogen, methyl or fluoro;R^(9d), R^(9e) and R^(9f) are each selected from hydrogen and fluoro;R^(5a), R^(5b), R^(6a) and R^(6b) are each independently selected fromthe group of hydrogen and C₁₋₃alkyl or CR^(5a)R^(6a) and CR^(5b)R^(6b)together form a C₃₋₇cycloalkyl radical;n is 0 or 1;whereineach Het¹ is a saturated heterocyclic radical selected frompyrrolidinyl; piperidinyl; piperazinyl; and morpholinyl; each of whichmay be optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of C₁₋₆alkyl, mono-, di- andtri-haloC₁₋₃alkyl, unsubstituted phenyl, and phenyl substituted with 1,2 or 3 substituents independently selected from the group consisting ofhalo, trifluoromethyl, and trifluoromethoxy; andeach Het² is an aromatic heterocyclic radical selected fromunsubstituted pyridinyl and pyrimidinyl;and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I′) andstereoisomeric forms thereof, wherein

is an N-containing heterocycle selected from the group consisting of

and the stereochemically isomeric forms thereof, whereinR¹ is selected from hydrogen; C₁₋₆alkyl; (C₁₋₃alkyloxy)C₁₋₃alkyl;[(C₁₋₃alkyloxy)-C₁₋₃alkyloxy]C₁₋₃alkyl; mono-, di- or tri-haloC₁₋₃alkyl;unsubstituted benzyl; benzyl substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halo, C₁₋₃alkyl,C₁₋₃alkyloxy, C₁₋₃alkyloxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl, cyano, hydroxyl,amino, C(═O)R′, C(═O)OR′, C(═O)NR′R″, mono- or di(C₁₋₃alkyl)amino,morpholinyl, (C₃₋₇cycloalkyl)C₁₋₃alkyloxy, trifluoromethyl andtrifluoromethoxy, wherein R′ and R″ are independently selected fromhydrogen and C₁₋₆alkyl; (benzyloxy)C₁₋₃alkyl; unsubstitutedC₃₋₇cycloalkyl; C₃₋₇cycloalkyl substituted with trihaloC₁₋₃alkyl;(C₃₋₇cycloalkyl)C₁₋₃alkyl;4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methyl; Het¹;Het¹C₁₋₃alkyl; Het² and Het²C₁₋₃alkyl;R² is selected from cyano; halo; mono-, di- or tri-haloC₁₋₃alkyl; mono-,di- and tri-haloC₁₋₃alkyloxy; C₁₋₃alkyl; C₃₋₇cycloalkyl; and(C₃₋₇cycloalkyl)C₁₋₃alkyl;R^(3a) is selected from unsubstituted phenyl; phenyl substituted with 1,2 or 3 substituents independently selected from the group consisting ofhalo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, mono-, di- and tri-haloC₁₋₃alkyl,cyano, hydroxyl, amino, carboxyl, C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy,mono-, di- or tri-haloC₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, mono- anddi(C₁₋₃alkyl)amino, and morpholinyl; unsubstituted benzyl; benzylsubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, mono-, di- ortri-haloC₁₋₃alkyl, cyano, hydroxyl, amino, carboxyl,C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy, mono-, di- andtri-haloC₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, mono- or di(C₁₋₃alkyl)amino,morpholinyl and (C₃₋₇cycloalkyl)C₁₋₃alkyloxy; phenyl with two vicinalsubstituents which taken together form a bivalent radical of formula

—N═CH—NH—  (a),

—CH═CH—NH—  (b), or

—O—CH₂—CH₂—NH—  (c);

morpholinyl; pyridinyl; pyrimidinyl; pyridinyloxy substituted with 1 or2 C₁₋₃alkyl groups; unsubstituted C₃₋₇cycloalkyl and C₃₋₇cycloalkylsubstituted with 1 or 2 substituents independently selected fromC₁₋₃alkyl, trihaloC₁₋₃alkyl and hydroxyl;R^(3b) is selected from unsubstituted phenyl; phenyl substituted with 1,2 or 3 substituents independently selected from the group consisting ofhalo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, mono-, di- and tri-haloC₁₋₃alkyl,cyano, hydroxyl, amino, carboxyl, C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy,mono-, di- or tri-haloC₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, mono- anddi(C₁₋₃alkyl)amino, and morpholinyl; unsubstituted benzyl; benzylsubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, mono-, di- ortri-haloC₁₋₃alkyl, cyano, hydroxyl, amino, carboxyl,C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy, mono-, di- andtri-haloC₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, mono- or di(C₁₋₃alkyl)amino,morpholinyl and (C₃₋₇cycloalkyl)C₁₋₃alkyloxy; phenyl with two vicinalsubstituents which taken together form a bivalent radical of formula

—N═CH—NH—  (a),

—CH═CH—NH—  (b), or

—O—CH₂—CH₂—NH—  (c);

pyridinyl; pyrimidinyl; unsubstituted C₃₋₇cycloalkyl and C₃₋₇cycloalkylsubstituted with 1 or 2 substituents independently selected fromC₁₋₃alkyl, trihaloC₁₋₃alkyl and hydroxyl;R^(4a) is selected from hydrogen; halogen; trifluoromethyl;trifluoromethoxy; hydroxyl; C₁₋₃alkyl; C₁₋₃alkyloxy; hydroxyC₁₋₃alkyl;hydroxylC₁₋₃alkyloxy; fluoroC₁₋₃alkyl; fluoroC₁₋₃alkyloxy; cyano;unsubstituted phenyl; and phenyl substituted with 1 or 2 substituentsindependently selected from the group consisting of halo, C₁₋₃alkyloxy,hydroxyC₁₋₃alkyl, trifluoromethyl and trifluoromethoxy;orR^(3a)—C—R^(4a) together represent a radical of formula (d′) or (e′) or(f′) or (g′)whereinW^(1d), W^(1e) and W^(1f) are each selected from CH or N;R^(7d), R^(7e), R^(7f), R^(8d), R^(8e) and R^(8f) are each independentlyselected from hydrogen, methyl or fluoro;R^(9d), R^(9e) and R^(9f) are each selected from hydrogen and fluoro;R^(5a), R^(5b), R^(6a) and R^(6b) are each independently selected fromthe group of hydrogen and C₁₋₃alkyl or CR^(5a)R^(6a) and CR^(5b)R^(6b)together form a C₃₋₇cycloalkyl radical;n is 0 or 1;whereineach Het¹ is a saturated heterocyclic radical selected frompyrrolidinyl; piperidinyl; piperazinyl; and morpholinyl; each of whichmay be optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of C₁₋₆alkyl, mono-, di- andtri-haloC₁₋₃alkyl, unsubstituted phenyl, and phenyl substituted with 1,2 or 3 substituents independently selected from the group consisting ofhalo, trifluoromethyl, and trifluoromethoxy; andeach Het² is an aromatic heterocyclic radical selected fromunsubstituted pyridinyl and pyrimidinyl;and the pharmaceutically acceptable salts and the solvates thereof.

In one embodiment, the invention relates to a compound according toFormula (I′) or a stereochemically isomeric form thereof, wherein

R¹ is selected from C₁₋₆alkyl; (C₁₋₃alkyloxy)C₁₋₃alkyl;[(C₁₋₃alkyloxy)C₁₋₃alkyloxy]-C₁₋₃alkyl; mono-, di- andtri-haloC₁₋₃alkyl; (benzyloxy)C₁₋₃alkyl; unsubstituted C₃₋₇cycloalkyl;C₃₋₇cycloalkyl substituted with trihaloC₁₋₃alkyl;(C₃₋₇cycloalkyl)-C₁₋₃alkyl;4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methyl; Het¹; andHet¹C₁₋₃alkyl,R² is cyano; halo or tri-haloC₁₋₃alkyl;R^(3a) and R^(3b) are each selected from unsubstituted phenyl; phenylsubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halo, hydroxyl-C₁₋₃alkyl, mono-, di- andtri-haloC₁₋₃alkyl, hydroxyl and C₁₋₃alkyloxy; unsubstituted benzyl;benzyl substituted with 1, 2 or 3 substituents independently selectedfrom halo, mono-, di- or tri-haloC₁₋₃alkyl, and(C₃₋₇cycloalkyl)C₁₋₃alkyloxy; morpholinyl; pyridinyl; pyrimidinyl;pyridinyloxy substituted with 1 or 2 C₁₋₃alkyl groups; andC₃₋₇cycloalkyl substituted with 1 or 2 substituents selected fromC₁₋₃alkyl, trihaloC₁₋₃alkyl and hydroxyl;R^(4a) is selected from hydrogen; halogen; trifluoromethyl;unsubstituted phenyl; and phenyl substituted with 1 or 2 substituentsindependently selected from the group consisting of halo, C₁₋₃alkyloxy,hydroxyC₁₋₃alkyl, trifluoromethyl and trifluoromethoxy;orR^(3a)—C—R^(4a) together represent a radical of formula (d) or (e) or(f) or (g)

whereinW^(1d), W^(1e) and W^(1f) are each selected from CH and N;R^(7d), R^(7e), R^(7f), R^(8d), R^(8e), R^(8f), R^(9d), R^(9e) andR^(9f) are as previously defined;R^(5a), R^(5b), R^(6a) and R^(6b) are each independently selected fromthe group of hydrogen and C₁₋₃alkyl;n is 0 or 1;Het¹ is as previously defined;or a pharmaceutically acceptable salt or a solvate thereof.

In the previous embodiment, R^(7d), R^(7e), R^(7f), R^(8d), R^(8e),R^(8f), R^(9d), R^(9e) and R^(9f) are preferably all hydrogen.

In the previous embodiment, R^(3a)—C—R^(4a) together preferablyrepresent a radical of formula (d) or (e), wherein W^(1d), W^(1e),R^(7d), R^(7e), R^(8d), R^(8e), R^(9d) and R^(9e) are as previouslydefined.

In an embodiment, the invention relates to a compound according toFormula (I) or a stereochemically isomeric form thereof, wherein

R¹ is selected from methyl; ethyl; propyl; n-butyl; 2-methylpropyl;tert-butyl; trifluoromethyl; 2,2,2-trifluoroethyl; 1,1-difluoroethyl;3,3,3-trifluoropropyl; methoxymethyl; ethoxymethyl;1-methyl-ethoxymethyl; methoxyethoxymethyl; unsubstituted cyclopropyl;cyclopropyl substituted with trifluoromethyl; unsubstituted cyclobutyl;cyclopropylmethyl; cyclobutylmethyl; phenylmethoxymethyl;pyrrolidinylmethyl; piperidinylmethyl; 4-phenyl-piperidinylmethyl;4-trifluoromethyl-piperidinylmethyl; morpholinylmethyl; and4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methyl;R² is cyano; chloro or trifluoromethyl;R^(3a) and R^(3b) are each selected from unsubstituted phenyl; phenylsubstituted with 1 or 2 substituents independently selected from thegroup consisting of fluoro, bromo, 2-hydroxy-2-propyl, methoxy,trifluoromethyl and hydroxyl; unsubstituted benzyl; benzyl substitutedwith 1 or 2 substituents independently selected from chloro,trifluoromethyl and cyclopropylmethyloxy; morpholinyl; pyridinyl;pyrimidinyl; pyridinyloxy substituted with 1 or 2 methyl groups; andcyclohexyl substituted with 1 or 2 substituents selected from methyl,trifluoromethyl and hydroxyl;R^(4a) is selected from hydrogen, fluoro, trifluoromethyl and phenyl;orR^(3a)—C—R^(4a) together represent a radical of formula (d-1) or (e-1)

R^(5a), R^(5b), R^(6a) and R^(6b) are each independently selected fromthe group of hydrogen and methyl;n is 0 or 1;or a pharmaceutically acceptable salt or a solvate thereof.

In the previous embodiment, R^(5a) and R^(6b), and R^(5b) and R^(6b) arepreferably both hydrogen or both methyl.

In an embodiment, the invention relates to a compound according toFormula (I) or a stereochemically isomeric form thereof, wherein

R¹ is selected from methyl; ethyl; propyl; n-butyl; 2-methylpropyl;tert-butyl; 2,2,2-trifluoroethyl; 1,1-difluoroethyl;3,3,3-trifluoropropyl; methoxymethyl; ethoxymethyl;1-methyl-ethoxymethyl; methoxyethoxymethyl; unsubstituted cyclopropyl;cyclopropyl substituted with trifluoromethyl; unsubstituted cyclobutyl;cyclopropylmethyl; cyclobutylmethyl; phenylmethoxymethyl;1-pyrrolidinylmethyl; 1-piperidinylmethyl; 4-phenyl-piperidinylmethyl;4-trifluoromethyl-piperidinylmethyl; and 4-morpholinylmethyl;R^(3a) and R^(3b) are each selected from unsubstituted phenyl;(2-hydroxy-2-propyl)phenyl; 3-fluoro-6-methoxy-phenyl;3-(trifluoromethyl)phenyl; 2,4-difluorophenyl;4-(trifluoromethyl)cyclohexyl; 2-fluoro-6-methoxyphenyl; 2-pyridinyl;3-methyl-2-pyridinyloxy; 4-hydroxy-4-methylcyclohexyl;3-fluoro-2-methoxy-phenyl; 3-chloro-4-(cyclopropylmethoxy)phenylmethyl;3-(trifluoromethyl)phenylmethyl; 4-morpholinyl; 2-pyrimidinyl;3-fluoro-6-hydroxyphenyl and 3-bromo-5-fluoro-2-methoxyphenyl;R^(4a) is selected from hydrogen, fluoro, trifluoromethyl and phenyl;orR^(3a)—C—R^(4a) together represent a radical of formula (d-1) or (e-1)

R^(5a) and R^(6a) and R^(5b) and R^(6b) are both hydrogen or bothmethyl;and n and R² are as previously defined;or a pharmaceutically acceptable salt or a solvate thereof.

In a further embodiment, the invention relates to compounds according toany of the other embodiments, wherein

R¹ is selected from C₁₋₆alkyl; (C₁₋₃alkyloxy)C₁₋₃alkyl;[(C₁₋₃alkyloxy)-C₁₋₃alkyloxy]C₁₋₃alkyl; mono-, di- or tri-haloC₁₋₃alkyl;unsubstituted benzyl; benzyl substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halo, C₁₋₃alkyl,C₁₋₃alkyloxy, C₁₋₃alkyloxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl, cyano, hydroxyl,amino, C(═O)R′, C(═O)OR′, C(═O)NR′R″, mono- or di(C₁₋₃alkyl)amino,morpholinyl, (C₃₋₇cycloalkyl)C₁₋₃alkyloxy, trifluoromethyl andtrifluoromethoxy, wherein R′ and R″ are independently selected fromhydrogen and C₁₋₆alkyl; (benzyloxy)C₁₋₃alkyl, unsubstitutedC₃₋₇cycloalkyl; C₃₋₇cycloalkyl substituted with trihaloC₁₋₃alkyl;(C₃₋₇cycloalkyl)C₁₋₃alkyl; Het² and Het²C₁₋₃alkyl;andR² is selected from halo; mono-, di- or tri-haloC₁₋₃alkyl; mono-, di-and tri-haloC₁₋₃alkyloxy; C₁₋₃alkyl; C₃₋₇cycloalkyl; and(C₃₋₇cycloalkyl)C₁₋₃alkyl;and the rest of the variables are as previously defined;and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 or 1;-   R¹ is selected from the group consisting of C₁₋₆alkyl; mono-, di- or    tri-haloC₁₋₃alkyl; and (C₃₋₇cycloalkyl)C₁₋₃alkyl;-   R² is selected from halo, C₁₋₃alkyl, and mono-, di- or    tri-haloC₁₋₃alkyl;

-   is selected from (L-a′) and (L-b′); wherein-   R^(3a) is selected from the group consisting of unsubstituted    phenyl; phenyl substituted with 1 or 2 halo substituents; pyridinyl;    and pyrimidinyl;-   R^(4a) is selected from hydrogen; halo and C₁₋₃alkyl;-   or CR^(3a)R^(4a) forms a radical of formula (d′); wherein-   W^(1d) is CH;-   R^(7d) and R^(8d) are both methyl;-   R^(9d) is fluoro;-   R^(3b) is phenyl substituted with 1 or 2 halo substituents;-   R^(5a), R^(5b), R^(6a) and R^(6b) are hydrogen; and-   halo is fluoro or chloro;-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the invention relates to compounds of Formula (I) andstereochemically isomeric forms thereof, wherein

-   n is selected from 0 and 1;-   R¹ is selected from the group consisting of mono-, di- or    tri-haloC₁₋₃alkyl; and (C₃₋₇cycloalkyl)C₁₋₃alkyl;-   R² is selected from halo and mono-, di- or tri-haloC₁₋₃alkyl;

-   is selected from (L-a′) and (L-b′); wherein-   R^(3a) is selected from the group consisting of unsubstituted    phenyl; and phenyl substituted with 1 or 2 halo substituents;-   R^(4a) is hydrogen, fluoro or methyl;-   or CR^(3a)R^(4a) forms a radical of formula (d′); wherein-   W^(1d) is CH;-   R^(7d) and R^(8d) are both methyl;-   R^(9d) is fluoro;-   R^(3b) is phenyl substituted with 1 or 2 halo substituents;-   R^(5a), R^(5b), R^(6a) and R^(6b) are hydrogen; and-   halo is fluoro or chloro;-   and the pharmaceutically acceptable salts and the solvates thereof.

In a further embodiment, the invention relates to compounds according toany of the other embodiments wherein R¹ is 2,2,2-trifluoroethyl, propylor cyclopropylmethyl.

In a further embodiment, the invention relates to compounds according toany one of the other embodiments wherein R² is chloro, methyl ortrifluoromethyl.

In a further embodiment, the L substituent may be selected from one ormore of the following:

wherein all variables are as previously defined.

In a further particular embodiment, the L substituent may be selectedfrom one or more of the following:

wherein all variables are as previously defined.

In a further particular embodiment, the L substituent may be selectedfrom (L-a1) and (L-b1).

In a particular embodiment, R^(3a)—C—R^(4a) may be selected from one ormore of the following:

In a particular embodiment, R^(3a)—C—R^(4a) is selected from any one of(d-1); (d-2); (d-3); (d-4); (d-5); (d-6); (e-1); (e-2); (e-3); (g-1);(g-2); (g-3); (g-4); (g-5) and (h).

Particular preferred compounds of formula (I) may be selected from thegroup of:

-   8-chloro-3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-1,2,4-triazolo-[4,3-a]pyridine,-   3-ethyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-methyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   7-(4-phenyl-1-piperidinyl)-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-cyclobutyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-ethyl-7-[4-(3-fluoro-2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-chloro-7-(4-phenyl-1-piperidinyl)-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[4-(3-fluoro-2-methoxyphenyl)-1-piperidinyl]-3-propyl-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(methoxymethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitiile,-   8-chloro-3-ethyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[4-(3-fluoro-2-methoxyphenyl)-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   7-(4-phenyl-1-piperidinyl)-3-propyl-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-cyclopropyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-chloro-7-[(4-phenyl-1-piperidinyl)methyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo-[4,3-a]pyridine,-   7-(4-phenyl-1-piperidinyl)-3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazolo[4,3-a]-pyridine-8-carbonitrile,-   3-[(phenylmethoxy)methyl]-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(1,1-difluoroethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(4-morpholinylmethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(cyclobutylmethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(1,1-dimethyl    ethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   7-(4-phenyl-1-piperidinyl)-3-(1-pyrrolidinylmethyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   7-(4-phenyl-1-piperidinyl)-3-[[4-(trifluoromethyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   7-(4-phenyl-1-piperidinyl)-3-[(4-phenyl-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]-pyridine-8-carbonitrile,-   7-(4-phenyl-1-piperidinyl)-3-(2,2,2-trifluoroethyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[3-(trifluoromethyl)phenyl]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(4-fluoro-4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(2,4-difluorophenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-(4-fluoro-4-phenyl-1-piperidinyl)-1,2,4-triazolo-[4,3-a]pyridine,-   8-chloro-7-(4-fluoro-4-phenyl-1-piperidinyl)-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo-[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-[cis-4-(trifluoromethyl)cyclohexyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(cyclopropylmethyl)-7-[4-[trans-4-(trifluoromethyl)cyclohexyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(5-fluoro-2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(2-pyridinyl)-1-piperidinyl]-1,2,4-triazolo-[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[(3-methyl-2-pyridinyl)oxy]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(trans-4-hydroxy-4-methylcyclohexyl)-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(cyclopropylmethyl)-7-[4-(cis-4-hydroxy-4-methylcyclohexyl)-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-alpha,alpha-dimethyl-benzenemethanol,-   8-chloro-3-(ethoxymethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[4-(2-fluoro-6-methoxyphenyl)-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   7-[4-[[3-chloro-4-(cyclopropylmethoxy)phenyl]methyl]-1-piperazinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-chloro-3-[(2-methoxyethoxy)methyl]-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo-[4,3-a]pyridine,-   7-(4-fluoro-4-phenyl-1-piperidinyl)-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(2-fluoro-6-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[4-(2-pyridinyl)-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]-pyridine,-   1′-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′-piperidine],-   3-(cyclopropylmethyl)-7-[4-(2-fluoro-6-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(2,2,2-trifluoroethyl)-7-[4-[cis-4-(trifluoromethyl)cyclohexyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-chloro-7-[4-[(3-methyl-2-pyridinyl)oxy]-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(2,2,2-trifluoroethyl)-7-[4-[[3-(trifluoromethyl)phenyl]methyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-chloro-7-[4-(5-fluoro-2-methoxyphenyl)-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(4-morpholinyl)-4-phenyl-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[4-(2-pyrimidinyl)-1-piperazinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo-[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(2-pyrimidinyl)-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[4-(2-fluoro-6-methoxyphenyl)-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-ethyl-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-(4-phenyl-1-piperidinyl)-3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-butyl-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-[(3-methyl-2-pyridinyl)oxy]-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-4-fluoro-phenol,-   7-[4-(3-bromo-5-fluoro-2-methoxyphenyl)-1-piperidinyl]-8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-(4-phenyl-1-piperidinyl)-3-(3,3,3-trifluoropropyl)-1,2,4-triazolo[4,3-a]-pyridine,-   1′-[8-chloro-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′-piperidine],-   8-chloro-3-(2-methylpropyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-   3-(cyclopropylmethyl)-7-(4-fluoro-4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(3,3-dimethyl-4-phenyl-1-piperazinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-phenyl-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   7-(4-fluoro-4-phenyl-1-piperidinyl)-3-[(1-methylethoxy)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[benzofuran-3(2H),4′-piperidine],-   3-(cyclopropylmethyl)-7-(3,3-dimethyl-4-phenyl-1-piperazinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(2,2,2-trifluoroethyl)-7-[4-[trans-4-(trifluoromethyl)cyclohexyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   3-(2-methylpropyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   rac-(2aα,3α,3aα)-3-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   3-(cyclopropylmethyl)-7-(4-phenyl-1-piperazinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′-piperidine],-   3-(cyclopropylmethyl)-7-[4-(2-pyridinyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[1,4-benzodioxin-2(3H),4′-piperidine],-   3-[(cyclopropylmethoxy)methyl]-7-(4-fluoro-4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   rac-(2aα,3α,3aα)-3-[8-chloro-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   8-chloro-3-(ethoxymethyl)-7-[4-(2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(ethoxymethyl)-7-[4-(5-fluoro-2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[4-(2,3-difluoro-6-methoxyphenyl)-1-piperidinyl]-3-(ethoxymethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[4-(2,4-difluoro-6-methoxyphenyl)-1-piperidinyl]-3-(ethoxymethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[4-(3,6-difluoro-2-methoxyphenyl)-1-piperidinyl]-3-(ethoxymethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[benzofuran-3(2H),4′-piperidine],-   1′-(8-chloro-3-propyl-1,2,4-triazolo[4,3-a]pyridin-7-yl)-spiro[benzofuran-3(2H),4′-piperidine],-   1′-[3-ethyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[benzofuran-3(2H),4′-piperidine],-   3-(cyclopropylmethyl)-7-[4-(5-methoxy-2-pyrimidinyl)-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(3-methoxy-2-pyridinyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(3-methoxy-2-pyridinyl)-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-(8-chloro-3-propyl-1,2,4-triazolo[4,3-a]pyridin-7-yl)-spiro[isobenzofuran-1(3H),4′-piperidine],-   1′-[8-chloro-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[1,4-benzodioxin-2(3H),4′-piperidine],-   8-chloro-7-[4-(2,4-difluorophenyl)-1-piperazinyl]-3-propyl-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[[trans-2-phenylcyclopropyl]methyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[4-(2,4-difluorophenyl)-1-piperazinyl]-3-(2,2,2-trifluoro    ethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[8-chloro-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[benzofuran-3(2H),4′-piperidine],-   8-chloro-3-(cyclopropylmethyl)-7-(4-phenyl-1-piperazinyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-(3,3-dimethyl-4-phenyl-1-piperazinyl)-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-(4-phenyl-1-piperazinyl)-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-(8-chloro-3-ethyl-1,2,4-triazolo[4,3-a]pyridin-7-yl)-spiro[isobenzofuran-1(3H),4′-piperidine],-   8-chloro-7-(3,3-dimethyl-4-phenyl-1-piperazinyl)-3-(ethoxymethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   8-chloro-3-(cyclopropylmethyl)-7-(3,3-dimethyl-4-phenyl-1-piperazinyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-(8-chloro-3-propyl-1,2,4-triazolo[4,3-a]pyridin-7-yl)-4-fluoro-spiro[isobenzofuran-1(3H),4′-piperidine],-   1′-(8-chloro-3-propyl-1,2,4-triazolo[4,3-a]pyridin-7-yl)-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   1′-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-fluoro-spiro[isobenzofuran-1(3H),4′-piperidine].1HCl.1.5    H₂O,-   1′-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-fluoro-spiro[isobenzofuran-1(3H),4′-piperidine],-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-fluoro-spiro[isobenzofuran-1(3H),4′-piperidine],-   4-fluoro-1′-[3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′-piperidine],-   3-(cyclopropylmethyl)-7-[4-(5-methoxy-2-pyrimidinyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   3,3-dimethyl-1′-[3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′-piperidine],-   8-chloro-7-[4-(2-pyridinyloxy)-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(ethoxymethyl)-7-[4-(4-fluorophenyl)-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(4-fluorophenyl)-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(3-fluorophenyl)-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   2-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-1,2,3,4-tetrahydro-isoquinoline,-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[furo[2,3-b]pyridine-3(2H),4′-piperidine],-   3-(cyclopropylmethyl)-7-[4-phenyl-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   7-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-phenyl-4,7-diazaspiro[2.5]octane,-   3-[(1-methylethoxy)methyl]-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(2-cyclopropylethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(2-pyridinyloxy)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[furo[2,3-b]pyridine-3(2H),4′-piperidine],-   1′-[8-chloro-3-(ethoxymethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[furo[2,3-b]pyridine-3(2H),4′-piperidine],-   8-chloro-7-(4-fluoro-4-phenyl-1-piperidinyl)-3-[(1-methylethoxy)methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[(3R)-3-methyl-4-phenyl-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(2-cyclopropylethyl)-7-[4-(2-pyridinyloxy)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(1,3-dihydro-2H-isoindol-2-yl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[(3S)-3-methyl-4-phenyl-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(ethoxymethyl)-7-[4-(2-pyridinyloxy)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-(4-methyl-4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(ethoxymethyl)-7-[4-[(3-methyl-2-pyridinyl)oxy]-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-[(1-methylethoxy)methyl]-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(ethoxymethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(3-phenyl-1-azetidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[8-chloro-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[furo[2,3-b]pyridine-3(2H),4′-piperidine],-   1′-[8-chloro-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   8-chloro-3-(2-cyclopropylethyl)-7-(4-fluoro-4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(ethoxymethyl)-7-(4-fluoro-4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3,3-difluoro-1′-[3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′-piperidine],-   1′-(8-chloro-3-propyl-1,2,4-triazolo[4,3-a]pyridin-7-yl)-3,3-difluoro-spiro[isobenzofuran-1(3H),4′-piperidine],-   8-chloro-3-[(1-methylethoxy)methyl]-7-[4-phenyl-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-8-methyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(2-cyclopropylethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-3,3-difluoro-spiro[isobenzofuran-1(3H),4′-piperidine],-   3-(cyclopropylmethyl)-7-[4-methyl-4-(2-pyridinyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′-piperidin]-3-one,-   3-[(1-methylethoxy)methyl]-7-[4-(2-pyridinyloxy)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(4-methyl-4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[(3S)-3-phenoxy-1-pyrrolidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-(4-phenyl-1-piperidinyl)-3-(2-pyridinylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[3-(cyclopropylmethyl)-8-methyl-1,2,4-triazolo[4,3-a]pyridin-7-yl]-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   3-[(1-methylethoxy)methyl]-7-(4-phenyl-1-piperazinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(4-methyl-2-thiazolyl)-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   7-[4-(3-benzofuranyl)-1-piperazinyl]-8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(3-pyridinylmethoxy)-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-cyclopropyl-3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[8-cyclopropyl-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   1′-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[furo[3,2-b]pyridine-3(2H),4′-piperidine],-   3-[(1-methylethoxy)methyl]-7-[4-[(3-methyl-2-pyridinyl)oxy]-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(2,2,2-trifluoro-1-phenylethyl)-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(3,4-dihydro-2H-1-benzopyran-3-yl)-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-[(2-methyl-4-pyridinyl)oxy]-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   (rac)-cis-3-(cyclopropylmethyl)-7-[5-(2,4-difluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(3-pyridinyloxy)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-(3-methyl-4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(3-methyl-4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(3-pyridinyloxy)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-8-ethyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[(2-methyl-4-pyridinyl)oxy]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-(3-phenyl-1-pyrrolidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(3-phenyl-1-pyrrolidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-N-phenyl-4-piperidinamine,-   1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-N-(2-fluorophenyl)-4-piperidinamine,-   3-(2,2-dimethylpropyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-N-phenyl-4-piperidinamine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[(3,5-difluorophenyl)methyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[(3S)-4-(3,5-difluorophenyl)-3-methyl-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[(3S)-4-(3,5-difluorophenyl)-3-methyl-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[(3R)-4-(3,5-difluorophenyl)-3-methyl-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-N-(2-fluorophenyl)-4-piperidinamine,-   8-chloro-3-(cyclopropylmethyl)-7-[(3R)-4-(3,5-difluorophenyl)-3-methyl-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclobutylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   (rac)-cis-8-chloro-3-(cyclopropylmethyl)-7-[5-(2,4-difluorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-8-methyl-7-[4-phenyl-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   2-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-6-(2,4-difluorophenyl)-2,6-diazaspiro[3.5]nonane,-   1-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-N-(2-fluorophenyl)-3-azetidinamine,-   1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-N-(2-fluorophenyl)-3-azetidinamine,-   8-chloro-7-[(3S)-4-(3,5-difluorophenyl)-3-methyl-1-piperazinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[(3R)-4-(3,5-difluorophenyl)-3-methyl-1-piperazinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(2-fluorophenyl)-4-methyl-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(4-fluorophenyl)-4-methyl-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(2,4-difluorophenyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(2,4-difluorophenyl)-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(3-fluorophenyl)-4-methyl-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(3-pyridinyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(2-methyl-4-pyridinyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-5-fluoro-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   7-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-2-(2,4-difluorophenyl)-2,7-diazaspiro[3.5]nonane,-   8-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-2-(2,4-difluorophenyl)-2,8-diazaspiro[4.5]decane,-   1-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-N-(2,4-difluorophenyl)-4-piperidinamine,-   3-(cyclopropylmethyl)-7-[1-(2,4-difluorophenyl)-4-piperidinyl]-8-methyl-1,2,4-triazolo[4,3-a]pyridine,-   3-phenyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   7-(4-phenyl-1-piperidinyl)-3-(4-pyridinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile,-   8-bromo-3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine,-   cis-8-chloro-3-(cyclopropylmethyl)-7-[3-methyl-4-phenyl-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   cis-3-(cyclopropylmethyl)-7-[3-methyl-4-phenyl-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-2-(2,4-difluorophenyl)-2,7-diazaspiro[3.5]nonane,-   7-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-2-(2,4-difluorophenyl)-2,7-diazaspiro[3.5]nonan-1-one,-   3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine.1.8    HCl,-   3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[(2,4-difluorophenyl)methyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(2-phenylethyl)-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(2-phenylethyl)-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine.1    HCl,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[[3-(trifluoromethyl)phenyl]methyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-phenyl-4-(trifluoromethyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   3-(cyclopropylmethyl)-7-[[4-(4-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(2-phenylethyl)-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[cis-4-(trifluoromethyl)cyclohexyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-phenyl-4-(trifluoromethyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(4-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-[(2,4-difluorophenyl)methyl]-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-(3,3,3-trifluoropropyl)-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   1-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-N-(phenylmethyl)-4-piperidinamine,-   6-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-2-[(2,4-difluorophenyl)methyl]-2,6-diazaspiro[3.5]nonane,-   2-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-6-[(2,4-difluorophenyl)methyl]-2,6-diazaspiro[3.5]nonane,-   3-(cyclopropylmethyl)-7-[4-(3,5-difluorophenyl)-3,3-dimethyl-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-(3,5-difluoro-2-pyridinyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   1′-[[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   3-(cyclopropylmethyl)-7-(4,4-difluoro[1,4′-bipiperidin]-1′-yl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   6-[[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-2-(4-fluorophenyl)-2,6-diazaspiro[3.5]nonane,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(trifluoromethyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-(4,4-difluoro[1,4′-bipiperidin]-1′-yl)-1,2,4-triazolo[4,3-a]pyridine,-   6-[[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-2-(4-fluorophenyl)-2,6-diazaspiro[3.5]nonane,-   3-(cyclopropylmethyl)-7-[1-(4-phenyl-1-piperidinyl)ethyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-methoxyphenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   2-[[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-(4-fluorophenyl)-2,6-diazaspiro[3.5]nonane,-   3-(cyclopropylmethyl)-7-[[4-(2-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(3-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   2-[[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-1,2,3,4-tetrahydro-benzofuro[3,2-c]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-pyridinyloxy)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[1-(4-phenyl-1-piperidinyl)ethyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(3-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   2-[[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-1,2,3,4-tetrahydro-benzofuro[3,2-c]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(1H-indol-1-yl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   1′-[[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-spiro[1H-indene-1,4′-piperidine],-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4(1H-indol-1-yl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(4-fluoro-2-methoxyphenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-ethoxy-3-fluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   rac-(2aα,3α,3aα)-3-[[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   3-(cyclopropylmethyl)-7-[[4-(4,6-dimethyl-2-pyrimidinyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[(4-methoxy-4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,6-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(4,6-dimethyl-2-pyrimidinyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   1′-[[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-spiro[1H-indene-1,4′-piperidine],-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(4-fluoro-2-methoxyphenyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-ethoxy-3-fluorophenyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-fluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-ethoxy-3-fluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-pyridinyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(4-fluoro-2-methoxyphenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,6-difluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-[(2,4-difluorophenyl)methoxy]-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-74    [4-(2-fluorophenyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-74    [4-(2,6-difluorophenyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-ethoxy-3-fluorophenyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-[(2,4-difluorophenyl)methoxy]-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[(4-methoxy-4-phenyl-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-pyrimidinyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2-chlorophenyl)-1-piperidinyl]methyl]-3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-pyridinyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(4-fluoro-2-methoxyphenyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   rac-(2aα,3α,3aα)-3-[[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   8-chloro-7-[[4-(4-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-pyridinyloxy)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethoxy)-7-[4-(2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-methoxyphenyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[[4-(5-chloro-2-pyridinyl)-1-piperazinyl]methyl]-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(4-fluoro-2-methoxyphenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine.1.1HCl,-   3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   2-[[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-(4-fluorophenyl)-2,6-diazaspiro[3.5]nonane,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2,6-difluorophenyl)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-fluoro-6-methoxyphenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-fluoro-6-methoxyphenyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[[4-(2-chlorophenyl)-1-piperidinyl]methyl]-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[4-[[3,5-bis(trifluoromethyl)phenyl]methyl]-1-piperazinyl]-8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-1-piperazinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   (1R,6S)-3-[[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-phenyl-3-azabicyclo[4.1.0]heptane,    8-chloro-3-(cyclopropylmethyl)-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine,-   4-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-1-phenyl-2-piperazinone,-   8-chloro-3-(ethoxymethyl)-7-[4-phenyl-4-(trifluoromethyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[4-phenyl-4-(trifluoromethyl)-1-piperidinyl]-3-propyl-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[[4-(2-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-7-[[4-(3-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenoxy)-1-piperidinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenoxy)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-8-methyl-7-[(4-phenyl-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-8-methyl-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-8-methyl-1,2,4-triazolo[4,3-a]pyridine-   3-ethyl-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-3-ethyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-3-ethyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-   7-[(4-phenyl-1-piperidinyl)methyl]-3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine-   3-butyl-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-butyl-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-butyl-7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(2-methylpropyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-3-(2-methylpropyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-3-(2-methylpropyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-pyrimidinyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2-fluoro-6-methoxyphenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[4-[(1R)-1-(4-fluorophenyl)ethyl]-1-piperazinyl]-1,2,4-triazolo[4,3-a]pyridine,-   rac-(2aα,3α,3aα)-3-[[3-ethyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   rac-(2aα,3α,3aα)-3-[[3-(cyclopropylmethyl)-8-methyl-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   3-ethyl-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   rac-(2aα,3α,3aα)-6-phenyl-3-[[3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-3-azabicyclo[3.1.0]hexane,-   rac-(2aα,3α,3aα)-3-[[3-butyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-3-(ethoxymethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine.HCl,-   7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-3-(ethoxymethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-3-(ethoxymethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine.    HCl,-   7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-3-(ethoxymethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(4-bromophenyl)-1-piperidinyl]methyl]-3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,5-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(ethoxymethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine.HCl,-   3-(ethoxymethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-3-(2-methylpropyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   rac-(2aα,3α,3aα)-3-[[3-(2-methylpropyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-3-propyl-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-butyl-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-8-methyl-1,2,4-triazolo[4,3-a]pyridine,-   3-(ethoxymethyl)-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   rac-(2aα,3α,3aα)-3-[[3-(ethoxymethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-6-phenyl-3-azabicyclo[3.1.0]hexane,-   3-(cyclopropylmethyl)-7-[[4-(3,5-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,3-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(3,4-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(3,5-difluorophenyl)-3,3-dimethyl-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(4-chloro-2-fluorophenyl)-1-piperazinyl]methyl]-3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(2-chloro-4-fluorophenyl)-1-piperazinyl]methyl]-3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-bromo-3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(3,5-difluoro-2-pyridinyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(5-fluoro-2-pyridinyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   7-[[4-(5-chloro-2-pyridinyl)-1-piperazinyl]methyl]-3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-[(2,4-difluorophenoxy)methyl]-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(3,5-difluoro-2-pyridinyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(5-fluoro-2-pyridinyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(2-cyclopropylethyl)-7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(2,2-dimethylpropyl)-7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclobutylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,    and-   8-chloro-7-[[4-(5-chloro-2-pyridinyl)-1-piperazinyl]methyl]-3-(cyclopropylmethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridine,-   and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the compound of Formula (I) is selected from the groupof:

-   8-chloro-7-(4-fluoro-4-phenyl-1-piperidinyl)-3-(2,2,2-trifluoro    ethyl)-1,2,4-triazolo-[4,3-a]pyridine;-   3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine;-   3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine.1.1HCl;-   1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-5-fluoro-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],-   3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine.1.8HCl,-   3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   8-chloro-3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,-   3-(cyclopropylmethyl)-7-[[4-(4-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,    and-   3-(cyclopropylmethyl)-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,-   and the pharmaceutically acceptable salts and solvates thereof.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not, are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove or hereinafter are meant to comprise thetherapeutically active non-toxic acid and base addition salt forms whichthe compounds of Formula (I) are able to form. The pharmaceuticallyacceptable acid addition salts can conveniently be obtained by treatingthe base form with such appropriate acid. Appropriate acids comprise,for example, inorganic acids such as hydrohalic acids, e.g. hydrochloricor hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of Formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.primary, secondary and tertiary aliphatic and aromatic amines such asmethylamine, ethylamine, propylamine, isopropylamine, the fourbutylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline; the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like. Conversely the salt formcan be converted by treatment with acid into the free acid form.

The term solvate comprises the solvent addition forms as well as thesalts thereof, which the compounds of formula (I) are able to form.Examples of such solvent addition forms are e.g. hydrates, alcoholatesand the like.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. Radiolabelled compounds of Formula (I)may comprise a radioactive isotope selected from the group of ³H, ¹¹C,¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷ _(B)r and ⁸²Br. Preferably,the radioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

Preparation

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person. Inparticular, the compounds can be prepared according to the followingsynthesis methods.

The compounds of Formula (I) may be synthesized in the form of racemicmixtures of enantiomers which can be separated from one anotherfollowing art-known resolution procedures. The racemic compounds ofFormula (I) may be converted into the corresponding diastereomeric saltforms by reaction with a suitable chiral acid.

Said diastereomeric salt forms are subsequently separated, for example,by selective or fractional crystallization and the enantiomers areliberated therefrom by alkali. An alternative manner of separating theenantiomeric forms of the compounds of Formula (I) involves liquidchromatography using a chiral stationary phase. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically.

A. Preparation of the Final Compounds Experimental Procedure 1

Final compounds according to Formula (I) can be prepared following artknown procedures by cyclization of intermediate compound of Formula (II)in the presence of a halogenating agent such as for examplephosphorus(V)oxychloride (POCl₃) ortrichloroacetonitrile-triphenylphosphine mixture in a suitable solventsuch as for example DCE or CH₃CN stirred under microwave irradiation,for a suitable period of time that allows the completion of thereaction, such as for example 50 min at a temperature between 140-200°C.

Alternatively, final compounds of Formula (I) can be prepared by heatingthe intermediate compound of Formula (II) for a suitable period of timethat allows the completion of the reaction, such as for example 1h at atemperature between 140-200° C. In reaction scheme (1), all variablesare defined as in Formula (I).

Experimental Procedure 2

Final compounds according to Formula (I) can be prepared by art knownprocedures in analogy to the syntheses described in J. Org. Chem., 1966,31, 251, or J. Heterocycl. Chem., 1970, 7, 1019, by cyclization ofintermediate compounds of Formula (III) under suitable conditions in thepresence of a suitable ortho-ester of Formula (IV), wherein R¹ is asuitable substituent like for example a methyl group, according toreaction scheme (2). The reaction can be carried out in a suitablesolvent such as, for example, xylene. Typically, the mixture can bestirred for 1 to 48 h at a temperature between 100-200° C. In reactionscheme (2), all variables are defined as in Formula (I).

Alternatively, final compounds according to Formula (I) can be preparedby art known procedures in analogy to the synthesis described inTetrahedron Lett., 2007, 48, 2237-2240 by reaction of intermediatecompound of Formula (III) with carboxylic acids of Formula (V) or acidequivalents such as acid halides of Formula (VI) to afford finalcompounds of Formula (I). The reaction can be carried out using ahalogenating agent such as for exampletrichloroacetonitrile-triphenylphosphine mixture in the presence of asuitable solvent such as for example dichloroethane stirred at atemperature between 100-200° C. for 1 to 48 h or under microwaveirradiation for 20 min. In reaction scheme (2), all variables aredefined as in Formula (I).

Experimental Procedure 3

Final compounds according to Formula (I) can be prepared by art knownprocedures, by cyclization of intermediate compounds of Formula (VII)under suitable conditions in the presence of a suitable oxidising agentsuch as copper(II)chloride in a suitable solvent such as DMF, stirredfor 1 to 48 h at a temperature between r.t. and 200° C. In reactionscheme (3), all variables are defined as in Formula (I).

Experimental Procedure 4

Final compounds according to Formula (I) wherein R¹ is a Het¹-C₁alkyl ora 4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methyl substituent aspreviously defined, wherein Het¹ is bound through the Nitrogen atomhereby represented as

hereby named (I-a), can be prepared by art known procedures by reactionof intermediate compound of Formula (VIII) under standard Mannichconditions with intermediate compound of Formula (IX). The reaction canbe carried out in the presence of formaldehyde with a suitable solventsuch as for example acetic acid stirred at a suitable temperature, forexample 80° C. for a period of time that allows completion of thereaction, for example 16 h. In reaction scheme (4), all variables aredefined as in Formula (I).

Experimental Procedure 5

Alternatively, final compounds according to Formula (I) wherein R¹ is aHet¹-C₁alkyl or a 4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methylsubstituent as previously defined, wherein Het¹ is bound through theNitrogen atom, hereby named (I-a) can be prepared by reacting anintermediate of Formula (IX) with an intermediate of Formula (X) underreductive amination conditions that are known to those skilled in theart. This is illustrated in reaction scheme (5) wherein all variablesare defined as in Formula (I). The reaction may be performed, forexample, in the presence of triacetoxy borohydride in a suitablereaction-inert solvent such as, for example, DCE, at a suitabletemperature, typically at r.t., for a suitable period of time thatallows the completion of the reaction.

Experimental Procedure 6

The final compounds according to Formula (I), can be prepared byreacting an intermediate compound of Formula (XI) with a compound ofFormula (XII) according to reaction scheme (6), a reaction that isperformed in a suitable reaction-inert solvent, such as, for example,1,4-dioxane or mixtures of inert solvents such as, for example,1,4-dioxane/DMF, in the presence of a suitable base, such as, forexample, aqueous NaHCO₃ or Na₂CO₃, a Pd-complex catalyst such as, forexample, Pd(PPh₃)₄ under thermal conditions such as, for example,heating the reaction mixture at 150° C. under microwave irradiation, forexample for 10 minutes. In reaction scheme (6), all variables aredefined as in Formula (I) and halo is a group suitable for Pd mediatedcoupling with boronic acids or boronic esters, such as, for examplechloro, bromo or iodo. R¹⁰ and R¹¹ may be hydrogen or alkyl, or may betaken together to form for example a bivalent radical of formula—CH₂CH₂—, —CH₂CH₂CH₂—, or —C(CH₃)₂C(CH₃)₂—.

Experimental Procedure 7

Final compounds according to Formula (I) wherein n is 0, and

is a radical of formula (L-a), (L-b), (L-d), (L-e), (L-f), (L-g) and(L-h) hereby represented by

hereby named (I-b), can be prepared by reacting an intermediate compoundof Formula (XIII) with a compound of Formula (XIV) according to reactionscheme (7), a reaction that is performed in a suitable reaction-inertsolvent, such as, for example, 1,4-dioxane, in the presence of asuitable base, such as, for example, K₃PO₄, a Pd-complex catalyst suchas, for example, 2-(2′-di-tert-butylphosphine)biphenylpalladium(II)acetate, under thermal conditions such as, for example, heating thereaction mixture for example at 80° C. for 12 h. In reaction scheme (7),all variables are defined as in Formula (I) and halo is chloro, bromo oriodo, suitable for Pd-mediated coupling with amines.

Alternatively, compounds according to Formula (I-b) can be prepared byreacting an intermediate compound of Formula (XIII) with a compound ofFormula (XIV) according to reaction scheme (7), a reaction that isperformed in a suitable reaction-inert solvent, such as, for example,1,2-dimethoxyethane or acetonitrile, in the presence of a suitable base,such as, for example, Cs₂CO₃ or N,N-diisopropylethylamine, under thermalconditions such as, for example, heating the reaction mixture forexample at 180° C. under microwave irradiation for 45 min.

Alternatively, compounds according to Formula (I-b) can be prepared byreacting an intermediate compound of Formula (XIII) with a compound ofFormula (XIV) according to reaction scheme (5), a reaction that isperformed in a suitable reaction-inert solvent such as, for example,toluene, in the presence of a suitable base such as, for example, sodiumtert-butoxide, a metal-based catalyst, specifically a palladiumcatalyst, such as palladium(II)acetate, and a suitable ligand, such asfor example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-d]phenyl-phosphine] (BINAP),heating for a suitable period of time that allows the completion of thereaction, for example at 100° C. for 16 h in a sealed tube.

Reaction Scheme 7a represents an example for the preparation of acompound of formula (I-b′) wherein

is (L-a) or (L-b), by reaction of intermediate (XIII) with a reagentformula (XIV-a) wherein R^(3a)—C—R^(4a), R^(3b)—N, R^(5a), R^(6a),R^(5b) and R^(6b) are in general represented by R³—X—R⁴, R⁵ and R⁶, andall other variables are as previously defined.

Final compounds according to Formula (I) wherein n is 0, and

is (L-c), hereby named (I-b″), can be prepared by reacting anintermediate compound of Formula (XIII) with a reagent of formula(XIV-b) according to reaction scheme (7b), wherein R¹⁰ and R¹¹ are aspreviously defined, and PG represents a suitable protecting group, suchas tert-butyloxycarbonyl, a reaction that is performed in a suitablereaction-inert solvent, such as, for example, 1,4-dioxane, in thepresence of a suitable base, such as, for example, NaHCO₃, a Pd-complexcatalyst such as, for example, Pd(PPh₃)₄ under thermal conditions suchas, for example, heating the reaction mixture at a suitable temperature,for example at 150° C., under thermal conditions or microwaveirradiation for a time sufficient to drive the reaction to completion.In reaction scheme (7b), all variables are defined as in Formula (I) andhalo is chloro, bromo or iodo, suitable for Pd-mediated coupling.Hydrogenation and further functional group interconversion (F.G.I.)performed under conditions known to a skilled person, afford compound(1-b″).

Experimental Procedure 8

Final compounds according to Formula (I) wherein L is (L-b), herebyrepresented by (1-b″), can be prepared by reacting an intermediatecompound of Formula (XV) with a compound of Formula (XVI) according toreaction scheme (8), a reaction that is performed in a suitablereaction-inert solvent, such as, for example, 1,4-dioxane, in thepresence of a suitable base, such as, for example, K₃PO₄, a Pd-complexcatalyst such as, for example,2-(2¹-di-tert-butylphosphine)biphenylpalladium(II) acetate, underthermal conditions such as, for example, heating the reaction mixturefor example at 80° C. for 12 h. In reaction scheme (8), all variablesare defined as in Formula (I) and halo is chloro, bromo or iodo,suitable for Pd-mediated coupling with amines.

Alternatively, the reaction can be performed in a suitablereaction-inert solvent, such as, for example, 1,2-dimethoxyethane oracetonitrile, in the presence of a suitable base, such as, for example,Cs₂CO₃ or N,N-diisopropylethylamine, under thermal conditions such as,for example, heating the reaction mixture for example at 180° C. undermicrowave irradiation for 45 min.

Alternatively, the reaction can also be performed in a suitablereaction-inert solvent such as, for example, toluene, in the presence ofa suitable base such as, for example, sodium tert-butoxide, ametal-based catalyst, specifically a palladium catalyst, such aspalladium(II)acetate, and a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-d]phenyl-phosphine] (BINAP),heating for a suitable period of time that allows the completion of thereaction, for example at 100° C. for 16 h in a sealed tube.

Experimental Procedure 9

The final compounds according to Formula (I) wherein n=m=1 and L is(L-a), (L-b), (L-d), (L-e), (L-f), (L-g) or (L-h), hereby exemplified ingeneral for (L-a) and (L-b), hereby represented as (I-c), can beprepared by reacting an intermediate of Formula (XVII) with anintermediate of Formula (XIV) under reductive amination conditions thatare known by those skilled in the art. This is illustrated in reactionscheme (9) wherein all variables are defined as in Formula (I). Thereaction may be performed, for example, in the presence of sodiumtriacetoxy borohydride in a suitable reaction-inert solvent such as, forexample, 1,2-dichloroethane, at a suitable temperature, for example attemperature between r.t. and 150° C., either classical heating ormicrowave irradiation, for a suitable period of time that allows thecompletion of the reaction.

Experimental Procedure 10

Alternatively, final compounds according to Formula (I-c) can beprepared by reacting an intermediate of Formula (XVIII) with anintermediate of Formula (XIV) under alkylating conditions that are knownby those skilled in the art. This is illustrated in reaction scheme (10)wherein all variables are defined as in mentioned hereabove and X is agroup suitable for alkylation reactions such as for example halo,methylsulfonate or p-tolylsulfonate. The reaction may be performed, forexample, in the presence of a base such as for examplediisopropylethylamine in a suitable reaction solvent such as, forexample, DMF for a suitable period of time that allows the completion ofthe reaction at suitable temperature such as for example 120° C.

Experimental Procedure 11

The final compounds according to Formula (I), wherein n=m=1 and R² ishalogen hereby name (I-d), can be prepared by reacting an intermediatecompound of Formula (XIX) with a N-halosuccinimide reagent, such asN-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, accordingto reaction scheme (11). This reaction is performed in a suitablereaction-inert and aprotic solvent, such as, for example,dichloromethane or 1,2-dichloroethane, stirring the reaction mixture ata suitable temperature, typically at room temperature, for the requiredtime to achieve completion of the reaction, usually 1 hour. In reactionscheme (11), all other variables are defined as in Formula (I).

B. Preparation of the Intermediates Experimental Procedure 12

Intermediate compounds according to Formula (II) can be preparedfollowing conditions that are known to those skilled in the art byreacting an intermediate of Formula (III) with a carboxylic acid ofFormula (V) via an amide bond formation reaction in the presence of asuitable coupling reagent. This is illustrated in reaction scheme (6)wherein all variables are defined as in Formula (I).

Alternatively, intermediate compounds according to Formula (II) can beprepared by art known procedures by reacting an intermediate of Formula(III) with a carboxylic acid of formula (V). The reaction can be carriedout using a halogenating agent such as for example atrichloroacetonitrile-triphenylphosphine mixture in the presence of asuitable solvent such as for example dichloroethane stirred at atemperature between 100-200° C. for 1 to 48 h or under microwaveirradiation for 20 min. In reaction scheme (12), all variables aredefined as in Formula (I).

Alternatively, intermediate compounds according to Formula (II) can beprepared by art known procedures by reacting an intermediate of Formula(III) with an acid halide of formula (VI). The reaction can be carriedout using a inert-solvent such as for example DCM in the presence of abase such as for example TEA, for example at r.t. for a suitable periodof time that allows completion of the reaction. In reaction scheme (12),all variables are defined as in Formula (I).

Experimental Procedure 13

Intermediate compounds according to Formula (VII) can be preparedfollowing conditions that are known to those skilled in the art byreacting an intermediate of Formula (III) with an aldehyde of Formula(XX) via imine bond formation reaction. The reaction can be carried outusing a protic solvent such as for example EtOH, for example attemperature between r.t. and 150° C. for a suitable period of time thatallows completion of the reaction. In reaction scheme (13), allvariables are defined as in Formula (I).

Experimental Procedure 14

Intermediate compounds according to Formula (III) can be prepared byreacting an intermediate compound of Formula (XXI) with hydrazineaccording to reaction scheme (14), a reaction that is performed in asuitable reaction-inert solvent, such as, for example, ethanol or THFunder thermal conditions such as, for example, heating the reactionmixture for example at 160° C. under microwave irradiation for 20 min orclassical thermal heating at 90° C. for 16 h. In reaction scheme (14),all variables are defined as in Formula (I) and halo is chloro, bromo oriodo.

Experimental Procedure 15

Intermediate compounds according to Formula (XXI) wherein n is 0, and Lis selected from (L-a), (L-b), (L-d), (L-e), (L-g) and (L-h) herebynamed (XXI-a) can be prepared by reacting an intermediate compound ofFormula (XXII) with a compound of Formula (XIV) according to reactionscheme (15), a reaction that is performed in a suitable reaction-inertsolvent, such as, for example, acetonitrile, in the presence of asuitable base, such as, for example, N,N-diisopropylethylamine, underthermal conditions such as, for example, heating the reaction mixturefor example at 110° C. for 4 h. In reaction scheme (15), all variablesare defined as in Formula (I) and halo is chloro, bromo or iodo.

Experimental Procedure 16

Intermediate compounds according to Formula (XXI) wherein n is 1, herebynamed (XXI-b) can be prepared by reacting an intermediate of Formula(XXIII) with an intermediate of Formula (XIV) under reductive aminationconditions that are known to those skilled in the art. This isillustrated in reaction scheme (16) wherein all variables are defined asin Formula (I). The reaction may be performed, for example, in thepresence of triacetoxy borohydride in a suitable reaction-inert solventsuch as, for example, DCE, at a suitable temperature, typically at r.t.,for a suitable period of time that allows the completion of thereaction.

Experimental Procedure 17

Intermediate compounds according to Formula (XXIII) can be prepared byreacting an intermediate of Formula (XXII) under conditions that areknown to those skilled in the art. This is illustrated in reactionscheme (17) wherein all variables are defined as mentioned hereabove.The reaction may be performed, for example, by first converting the arylhalide into an aryl metal derivative where the metal may be lithium,magnesium, boron or zinc followed by reaction with the appropriatecarbonyl compound. Methods accomplishing these transformations are wellknown to those skilled in the art and include metal exchange with aGrignard reagent such as isopropylmagnesium chloride or strong base suchas for example BuLi in a suitable reaction inert solvent such as THF,diethyl ether or toluene, preferably THF at a temperature between −78°C. and 40° C., followed by reaction with the carbonyl compound such asfor example DMF at a temperature between −78° C. and 100° C.

Experimental Procedure 18

Intermediate compounds according to Formula (VIII) can be prepared byart known procedures in analogy to the syntheses described in J. Org.Chem., 1966, 31, 251, or J. Heterocyclic. Chem., 1970, 7, 1019, bycyclization of intermediate compounds of Formula (III) under suitableconditions in the presence of a suitable ortho-ester, for example, anorthoester of formula (IV) above, such as commercially availableexamples thereof wherein R¹ is H and R is methyl or ethyl, according toreaction scheme (18). The reaction can be carried out neat or in asuitable solvent such as, for example, xylene. Typically, the mixturecan be stirred for 1 to 48 h at a temperature between 100-200° C. Inreaction scheme (18), all variables are defined as in Formula (I).

Experimental Procedure 19

Intermediate compounds of Formula (X) can be prepared by reacting anintermediate compound of Formula (VIII) under standard Vilsmeier-Haackreaction conditions such as, for example, DMF andphosphorus(V)oxychloride (POCl₃) at a temperature from r.t. to 140° C.under classical thermal heating or under microwave irradiation, for asuitable period of time that allows the completion of the reaction, forexample 1 h. In reaction scheme (19), all variables are defined as inFormula (I).

Experimental Procedure 20

Intermediate compounds of Formula (XI) can be prepared by reacting anintermediate compound of Formula (VIII) under standard halogenationsstandard conditions such as, for example, DMF and N-bromosuccinimide ata temperature from r.t. to 140° C. under classical thermal heating orunder microwave irradiation, for a suitable period of time that allowsthe completion of the reaction, for example 1 h. In reaction scheme(20), all variables are defined as in Formula (I).

Experimental Procedure 21

Intermediate compounds according to Formula (XIII) can be preparedfollowing art known procedures by cyclization of an intermediatecompound of Formula (XXIV) in the presence of a halogenating agent suchas for example phosphorus(V) oxychloride (POCl₃) in a suitable solventsuch as, for example, dichloroethane, stirred under microwaveirradiation, for a suitable period of time that allows the completion ofthe reaction, as for example 5 min at a temperature between 140-200° C.In reaction scheme (21), all variables are defined as in Formula (I) andhalo is chloro, bromo or iodo.

Experimental Procedure 22

Alternatively, intermediate compounds of Formula (XIII) can be preparedfollowing art known procedures by cyclization of intermediate compoundof Formula (XXV) under heating for a suitable period of time that allowsthe completion of the reaction, as for example 1h at a temperaturebetween 140-200° C. In reaction scheme (22), all variables are definedas in Formula (I) and halo is chloro, bromo or iodo.

Experimental Procedure 23

Intermediate compounds according to Formula (XXIV) can be prepared byart known procedures by reaction of a hydrazine intermediate of Formula(XXVI) with acid halides of Formula (VI). The reaction can be carriedout using an inert-solvent, such as for example DCM, in the presence ofa base such as for example triethylamine, for example at r.t. for asuitable period of time that allows completion of the reaction, forexample 20 min. In reaction scheme (23), all variables are defined as inFormula (I).

Experimental Procedure 24

Intermediate compounds according to Formula (XXV) can be prepared by artknown procedures by reaction of intermediate compounds of Formula(XXVII) with acid halides of Formula (VI). The reaction can be carriedout using an inert-solvent such as for example DCM in the presence of abase such as for example triethylamine, for example at r.t. for asuitable period of time that allows completion of the reaction, forexample 20 min. In reaction scheme (24), all variables are defined as inFormula (I) and halo is chloro, bromo or iodo.

Experimental Procedure 25

Intermediate compounds according to Formula (XXVII) can be prepared byreacting an intermediate compound of Formula (XXII) with hydrazineaccording to reaction scheme (25), a reaction that is performed in asuitable reaction-inert solvent, such as, for example, ethanol, THF or1,4-dioxane under thermal conditions such as, for example, heating thereaction mixture for example at 160° C. under microwave irradiation for30 min or classical thermal heating at 70° C. for 16 h. In reactionscheme (25), R² is defined as in Formula (I) and halo is chloro, bromoor iodo.

Experimental Procedure 26

Intermediate compounds according to Formula (XXVI) can be prepared byreacting an intermediate compound of Formula (XXVIII) with hydrazineaccording to reaction scheme (26), a reaction that is performed in asuitable reaction-inert solvent, such as, for example, ethanol, THF or1,4-dioxane under thermal conditions such as, for example, heating thereaction mixture for example at 160° C. under microwave irradiation for30 min or classical thermal heating at 70° C. for 16 h. In reactionscheme (26), R² is defined as in Formula (I) and halo is chloro, bromoor iodo.

Experimental Procedure 27

Intermediate compounds according to Formula (XXVII) can be prepared byreacting an intermediate compound of Formula (XXII) with benzyl alcoholaccording to reaction scheme (27), a reaction that is performed in asuitable reaction-inert solvent, such as, for example,N,N-dimethylformamide in the presence of a suitable base, such as forexample sodium hydride at r.t. for a suitable period of time that allowsthe completion of the reaction, such as for example 1h. In reactionscheme (27), R² is defined as in Formula (I) and halo is chloro, bromoor iodo.

Experimental Procedure 28

Intermediate compounds of Formula (XXII) wherein R² is trifluoromethyl,hereby named (XXII-a), can be prepared by reacting an intermediate ofFormula (XXII) wherein R² is iodine, hereby named (XXII-b), with asuitable trifluoromethylating agent, such as for examplefluorosulfonyl(difluoro)acetic acid methyl ester, according to reactionscheme (28). This reaction is performed in a suitable reaction-inertsolvent such as, for example, N,N-dimethylformamide in the presence of asuitable coupling agent such as for example, copper iodide, underthermal conditions such as, for example, heating the reaction mixturefor example at 160° C. under microwave irradiation for 45 min. Inreaction scheme (28), halo is chloro, bromo or iodo.

Experimental Procedure 29

Intermediate compounds of Formula (XXII) wherein R² is iodine, herebynamed (XXII-b), can be prepared by reacting an intermediate compound ofFormula (XXVIII') with a strong base such as, for example,n-butyllithium, and further treatment with an iodinating agent such as,for example, iodine. This reaction is performed in a suitablereaction-inert solvent such as, for example, THF at low temperature suchas, for example −78° C. for a period of time that allows the completionof the reaction such as, for example 2 h. In reaction scheme (29), halomay be chloro, bromo or iodo

Experimental Procedure 30

Intermediate compounds of Formula (XXII) wherein R² is C₁₋₃alkyl,C₃₋₇cycloalkyl or (C₃₋₇cycloalkyl)C₁₋₃alkyl, hereby named (XXII-c), canbe prepared by an ortho metallation strategy by reacting an intermediateof Formula (XXVIII′) with a substituted or unsubstituted alkyl or analkenyl halide (XXIX) in the presence of a suitable base, such aslithium diisopropylamide or butyllithium, according to reaction scheme(30) and following references: a) Tetrahedron 2001, 57(19), 4059-4090 orb) Tetrahedron 2001, 57(21), 4489-4505. This reaction is performed in asuitable reaction-inert solvent such as, for example, THF at lowtemperature such as, for example −78° C. for a period of time thatallows the completion of the reaction such as, for example 2-5h. Inreaction scheme (30), halo may be chloro, bromo or iodo and E representsan appropriate C₁₋₃alkyl, C₃₋₇cycloalkyl or (C₃₋₇cycloalkyl)C₁₋₃alkylradical. If required, intermediates (XXII-c) may be subjected to furthersimple functional group interconversion steps following art-knownprocedures to lead to the desirable final R² group.

Experimental Procedure 31

Intermediate compounds of Formula (XXII) wherein R² is haloC₁₋₃alkoxy,hereby named (XXII-d), can be prepared for example by reacting anintermediate of formula (XXX) with a suitable alkyl or alkenyl halide(XXXI) in the presence of a suitable base such as potassium carbonate.This reaction is performed in a suitable reaction-inert solvent such as,for example, DMF under thermal conditions such as for example, heatingthe reaction mixture for example at 50-100° C. for a period of time thatallows the completion of the reaction such as for example, 2 h. Inreaction scheme (31), halo may be chloro, bromo or iodo and E′represents an appropriate C₁₋₃alkyl or C₂₋₃alkenyl radical, which may befurther halogenated following procedures known to those skilled in theart.

Experimental Procedure 32

Intermediate compounds according to Formula (XVII) can be prepared byreacting an intermediate of Formula (XXXII) under conditions that areknown to those skilled in the art and can be realized for example withoxone, osmium tetroxide. The process may be carried out optionally in asolvent such as 1,4-dioxane, water and generally at temperatures betweenabout −100° C. and about 100° C. A summary of such methods is found in“Comprehensive Organic Transformations”, VCH Publishers, (1989), R. C.Larock, pp. 595-596. This is illustrated in reaction scheme (32) whereinall variables are defined as mentioned hereabove.

Experimental Procedure 33

Intermediate compounds according to Formula (XXXII) can be prepared bycoupling reactions of an intermediate of Formula (XIII) with a compoundof Formula (XXXIII) under conditions that are known to those skilled inthe art. This is illustrated in reaction scheme (33) wherein allvariables are defined as mentioned hereabove, wherein M is trialkyltin,boronic acid or boronate ester, and a palladium catalyst. The processmay be carried out optionally in a solvent such as 1,4-dioxane, waterand generally at temperatures between about r.t and about 200° C. in thepresence of a base.

Experimental Procedure 34

Intermediate compounds according to Formula (XVIII) can be prepared fromconversion of the hydroxyl group present in intermediate compound ofFormula (XXXIV) into a suitable leaving group such as for examplehalogen or mesylate conditions that are known to those skilled in theart. The reaction may be performed, for example, by reacting anintermediate compound of Formula (XXXIV) with methyl sulfonic acidchloride in the presence of a base such as triethylamine, pyridine orhalogenating reagens such as for example P(O)Br₃ in a suitablereaction-inert solvent such as, for example, DCM or DMF or mixtures ofboth, at a suitable temperature, typically at room temperature, for asuitable period of time that allows the completion of the reaction.

Experimental Procedure 35

Intermediate compounds according to Formula (XXXIV) can be prepared byreacting an intermediate of Formula (XVII) under conditions that areknown to those skilled in the art. This is illustrated in reactionscheme (35) wherein all variables are defined as mentioned hereabove.The reaction may be performed, for example, by reacting intermediate ofFormula (XVII) with a reductive reagent such as for example sodiumborohydride in a suitable solvent such as for example methanol. Thereaction may be performed at a suitable temperature, typically roomtemperature, for a suitable period of time that allows the completion ofthe reaction. This is illustrated in reaction scheme (35) wherein allvariables are defined as mentioned hereabove

Experimental Procedure 36

Intermediate compounds of formula (XIX) as described in reaction scheme(11) can also be considered final compounds according to formula (I).The final compounds according to Formula (I-d), wherein n=m=1 and R² ishalo, can be converted to compounds of formula (XIX) under hydrogenationconditions or hydrogen-metal exchange, according to reaction scheme(36). This reaction is performed in a suitable reaction-inert andaprotic solvent, such as, for example, dichloromethane or1,2-dichloroethane, stirring the reaction mixture at a suitabletemperature, typically at room temperature, for the required time toachieve completion of the reaction, usually 1 hour. In reaction scheme(36), all other variables are defined as in Formula (I).

Experimental Procedure 37

The intermediate compounds according to Formula (XIII), wherein R² is analkyl, hereby named (XIII-b) can be prepared by reacting an intermediatecompound of Formula (XIII) wherein R² is an halo, hereby named (XIII-a)with a compound of Formula (XII) according to reaction scheme (37), areaction that is performed in a suitable reaction-inert solvent, suchas, for example, 1,4-dioxane or mixtures of inert solvents such as, forexample, 1,4-dioxane/DMF, in the presence of a suitable base, such as,for example, aqueous NaHCO₃ or Na₂CO₃, a Pd-complex catalyst such as,for example, Pd(PPh₃)₄ under thermal conditions such as, for example,heating the reaction mixture at 150° C. under microwave irradiation, forexample for 10 minutes. In reaction scheme (6), all variables aredefined as in Formula (I) and halo is a group suitable for Pd mediatedcoupling with boronic acids or boronic esters, such as, for examplechloro, bromo or iodo. R¹⁰ and R¹¹ may be hydrogen or alkyl, or may betaken together to form for example a bivalent radical of formula—CH₂CH₂—, —CH₂CH₂CH₂—, or —C(CH₃)₂C(CH₃)₂—.

Experimental Procedure 37

Intermediate compounds of Formula (XIV) can be prepared by deprotectionof the nitrogen atom in an intermediate compound of formula (XXXV),wherein PG represents a suitable protecting group for the nitrogen atom,such as for example tert-butoxycarbonyl, ethoxycarbonyl,benzyloxycarbonyl, benzyl and methyl, according to reaction scheme (37)applying art known procedures. For example, when PG represents benzyl,then the deprotection reaction may be performed in a suitable reactioninert solvent, such as for example an alcohol, i.e. methanol, and1,4-cyclohexadiene, in the presence of a suitable catalyst, such as forexample palladium on charcoal, at a moderately high temperature such as,for example, 100° C. in a sealed vessel. Alternatively, when PGrepresents an alkyloxycarbonyl group, the deprotection reaction can beperformed by reaction with a suitable acid, such as for examplehydrochloric acid, in a suitable reaction-inert solvent, such as forexample 1,4-dioxane at a moderately high temperature, such as forexample reflux temperature. In reaction scheme (37), all variables aredefined as in formula (I).

Experimental Procedure 38

Intermediate compounds of Formula (XIV) wherein R⁴ is CF₃, X is C and R⁵and R⁶ are H, hereby named (XIV-a), can be prepared by reacting anintermediate of Formula (XXXVI) according to reaction scheme (38), underconditions that are known to those skilled in the art [Bioorganic &Medicinal Chemistry 2006, 14, 2620-2626] by reduction of the phthalimidefunction with a reductive agent such as for example borane-THF in asuitable solvent such as, for example, THF, at a suitable temperature,typically at reflux, for a suitable period of time that allows thecompletion of the reaction. In reaction scheme (38), R³ is as defined inFormula (I).

Experimental Procedure 39

Intermediate compounds of Formula (XXXVI) can be prepared by reacting anintermediate of Formula (XXXVII) according to reaction scheme (39),under conditions that are known to those skilled in the art [Journal ofAntibiotics 1995, 48(10), 1179-81] by cyclization of the correspondingcarboxylic acid (XXXVII) by reaction with acetic anhydride and urea atreflux for a suitable period of time that allows the completion of thereaction. In reaction scheme (39), R³ is as defined in Formula (I)

Experimental Procedure 40

Intermediate compounds according to Formula (XXXVII) can be prepared byhydrolysis of an intermediate of formula (XXXVIII) according to reactionscheme (39), under conditions that are known to those skilled in the art[Journal of American Chem. Soc. 1958, 80, 3915-3923]. The hydrolysis ofintermediate of Formula (XXXVIII) may be performed in alkaline solutionsuch as for example sodium hydroxide followed by a brief period ofreflux in acid solution such as for example sulfuric acid. Bothreactions are heated typically at reflux, for a suitable period of timethat allows the completion of the reaction. In reaction scheme (40), R³is as defined in Formula (I).

Experimental Procedure 41

Intermediate compounds according to Formula (XXXVIII) can be prepared byreaction of an intermediate of formula (XXXIX) according to reactionscheme (41), under conditions that are known to those skilled in the art[J. Am. Chem. Soc. 1958, 80, 3915-3923], by hydrolysis of anintermediate of Formula (XXXVIII) in the presence of suitable acids suchas a mixture of sulfuric acid, acetic acid and water at a suitabletemperature, typically at reflux, for a suitable period of time thatallows the completion of the reaction. In reaction scheme (41), R³ is asdefined in Formula (I).

Experimental Procedure 41a

Intermediate compounds according to Formula (XXXVIII) can be preparedfrom intermediate compound (XXXIX) according to reaction scheme (41a),by reacting intermediate of Formula (XXXIX) with cyanoacetamide (XL)under conditions that are known to those skilled in the art [J. Am.Chem. Soc. 1958, 80, 3915-3923]. The reaction may be performed, forexample, in the presence of a suitable base such as for example sodiumethoxyde, in a suitable reaction-inert solvent such as, for example,EtOH, at a suitable temperature, typically r.t., for a suitable periodof time that allows the completion of the reaction. In reaction scheme(41a), R³ is as defined in Formula (I).

Experimental Procedure 42

Intermediate compounds according to Formula (XXXIX) can be prepared byreacting an intermediate of Formula (XLI) with cyanoacetate (XLII)according to reaction scheme (42), under Knoevenagel condensationconditions that are known to those skilled in the art [J. Am. Chem. Soc.1958, 80, 3915-3923]. The reaction may be performed, for example, in thepresence of titanium tetrachloride, a suitable base such as for examplepyridine and a suitable reaction-inert solvent such as, for example,DCM, at a suitable temperature, typically at r.t., for a suitable periodof time that allows the completion of the reaction. In reaction scheme(42), R³ is as defined in Formula (I).

The starting materials according to Formulae (IV), (V), (VI), (IX),(XII), (XIV), (XVI), (XXII), (XXVIII), XXIX), (XXX), (XXXI), (XXXIII),(XL), (XLI), (XXXIII), XL, (XLI) or (XLII) are compounds that are eithercommercially available or may be prepared according to conventionalreaction procedures generally known to those skilled in the art.

In order to obtain the HCl salts forms of the compounds, severalprocedures known to those skilled in the art can be used. In a typicalprocedure, for example, the free base can be dissolved in DIPE or Et₂Oand subsequently, a 6N HCl solution in 2-propanol or a 1 N HCl solutionin Et₂O can be added dropwise. The mixture typically is stirred for 10min after which the product can be filtered off. The HCl salt is usuallydried in vacuo.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups. In case the functional groups ofintermediate compounds were blocked by protecting groups, they can bedeprotected after a reaction step.

Pharmacology

The compounds provided in this invention are positive allostericmodulators (PAMs) of metabotropic glutamate receptors, in particularthey are positive allosteric modulators of mGluR2. The compounds of thepresent invention do not appear to bind to the glutamate recognitionsite, the orthosteric ligand site, but instead to an allosteric sitewithin the seven transmembrane region of the receptor. In the presenceof glutamate or an agonist of mGluR2, the compounds of this inventionincrease the mGluR2 response. The compounds provided in this inventionare expected to have their effect at mGluR2 by virtue of their abilityto increase the response of such receptors to glutamate or mGluR2agonists, enhancing the response of the receptor.

As used herein, the term “treatment” is intended to refer to allprocesses, wherein there may be a slowing, interrupting, arresting orstopping of the progression of a disease, but does not necessarilyindicate a total elimination of all symptoms.

Hence, the present invention relates to a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for use as a medicament.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention forthe manufacture of a medicament.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms thereof and the pharmaceuticallyacceptable acid or base addition salts and the solvates thereof, or apharmaceutical composition according to the invention for use in thetreatment or prevention of, in particular treatment of, a condition in amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of allostericmodulators of mGluR2, in particular positive allosteric modulatorsthereof.

The present invention also relates to the use of a compound according tothe general Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention forthe manufacture of a medicament for the treatment or prevention of, inparticular treatment of, a condition in a mammal, including a human, thetreatment or prevention of which is affected or facilitated by theneuromodulatory effect of allosteric modulators of mGluR2, in particularpositive allosteric modulators thereof.

The present invention also relates to a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention foruse in the treatmen, prevention, amelioration, control or reduction ofthe risk of various neurological and psychiatric disorders associatedwith glutamate dysfunction in a mammal, including a human, the treatmentor prevention of which is affected or facilitated by the neuromodulatoryeffect of positive allosteric modulators of mGluR2.

The present invention also relates to a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention foruse in the treatment, prevention, amelioration, control or reduction ofthe risk of various neurological and psychiatric disorders associatedwith glutamate dysfunction in a mammal, including a human, the treatmentor prevention or which is altered or facilitated by the neuromodulatoryeffect of positive allosteric modulators of mGluR2.

Also, the present invention relates to the use of a compound accordingto the general Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, or a pharmaceutical composition according to the invention forthe manufacture of a medicament for treating, preventing, ameliorating,controlling or reducing the risk of various neurological and psychiatricdisorders associated with glutamate dysfunction in a mammal, including ahuman, the treatment or prevention of which is affected or facilitatedby the neuromodulatory effect of positive allosteric modulators ofmGluR2.

In particular, the neurological and psychiatric disorders associatedwith glutamate dysfunction, include one or more of the followingconditions or diseases: acute neurological and psychiatric disorderssuch as, for example, cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine(including migraine headache), urinary incontinence, substancedependence/abuse, substance withdrawal (including substances such as,for example, opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder), mood disorders (includingdepression, major depressive disorder, treatment resistant depression,mania, bipolar disorders, such as bipolar mania), posttraumatic stressdisorder, trigeminal neuralgia, hearing loss, tinnitus, maculardegeneration of the eye, emesis, brain edema, pain (including acute andchronic states, severe pain, intractable pain, neuropathic pain, andpost-traumatic pain), tardive dyskinesia, sleep disorders (includingnarcolepsy), attention deficit/hyperactivity disorder, and conductdisorder.

In particular, the condition or disease is a central nervous systemdisorder selected from the group of anxiety disorders, psychoticdisorders, personality disorders, substance-related disorders, eatingdisorders, mood disorders, migraine, epilepsy or convulsive disorders,childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia.

Preferably, the central nervous system disorder is an anxiety disorder,selected from the group of agoraphobia, generalized anxiety disorder(GAD), mixed anxiety and depression, obsessive-compulsive disorder(OCD), panic disorder, posttraumatic stress disorder (PTSD), socialphobia and other phobias.

Preferably, the central nervous system disorder is a psychotic disorderselected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder.

Preferably, the central nervous system disorder is a personalitydisorder selected from the group of obsessive-compulsive personalitydisorder and schizoid, schizotypal disorder.

Preferably, the central nervous system disorder is a substance abuse orsubstance-related disorder selected from the group of alcohol abuse,alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium,alcohol-induced psychotic disorder, amphetamine dependence, amphetaminewithdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence,nicotine withdrawal, opioid dependence and opioid withdrawal.

Preferably, the central nervous system disorder is an eating disorderselected from the group of anorexia nervosa and bulimia nervosa.

Preferably, the central nervous system disorder is a mood disorderselected from the group of bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder,treatment resistant depression, bipolar depression, andsubstance-induced mood disorder.

Preferably, the central nervous system disorder is migraine.

Preferably, the central nervous system disorder is epilepsy or aconvulsive disorder selected from the group of generalized nonconvulsiveepilepsy, generalized convulsive epilepsy, petit mal status epilepticus,grand mal status epilepticus, partial epilepsy with or withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, and other forms of epilepsy.

Preferably, the central nervous system disorder isattention-deficit/hyperactivity disorder.

Preferably, the central nervous system disorder is a cognitive disorderselected from the group of delirium, substance-induced persistingdelirium, dementia, dementia due to HIV disease, dementia due toHuntington's disease, dementia due to Parkinson's disease, dementia ofthe Alzheimer's type, behavioral and psychological symptoms of dementia,substance-induced persisting dementia and mild cognitive impairment.

Of the disorders mentioned above, the treatment of psychosis, such asschizophrenia, behavioral and psychological symptoms of dementia, majordepressive disorder, treatment resistant depression, bipolar depression,anxiety, depression, generalised anxiety disorder, post-traumatic stressdisorder, bipolar mania, substance abuse and mixed anxiety anddepression, are or particular importance.

Of the disorders mentioned above, the treatment of anxiety,schizophrenia, migraine, depression, and epilepsy are of particularimportance.

At present, the fourth edition of the Diagnostic & Statistical Manual ofMental Disorders (DSM-IV) of the American Psychiatric Associationprovides a diagnostic tool for the identification of the disordersdescribed herein. The person skilled in the art will recognize thatalternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders described herein exist, and thatthese evolve with medical and scientific progresses.

Therefore, the invention also relates to a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for use in the treatment of any one of the diseases mentionedhereinbefore.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms thereof and the pharmaceuticallyacceptable acid or base addition salts and the solvates thereof, for usein treating any one of the diseases mentioned hereinbefore.

The invention also relates to a compound according to the generalFormula (I), the stereoisomeric forms thereof and the pharmaceuticallyacceptable acid or base addition salts and the solvates thereof, for thetreatment or prevention, in particular treatment, of any one of thediseases mentioned hereinbefore.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for the manufacture of a medicament for the treatment orprevention of any one of the disease conditions mentioned hereinbefore.

The invention also relates to the use of a compound according to thegeneral Formula (I), the stereoisomeric forms thereof and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, for the manufacture of a medicament for the treatment of anyone of the disease conditions mentioned hereinbefore.

The compounds of the present invention can be administered to mammals,preferably humans, for the treatment or prevention of any one of thediseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from any one of the diseases mentioned hereinbefore, and amethod of preventing in warm-blooded animals, including humans, any oneof the diseases mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topicaladministration, preferably oral administration, of a therapeuticallyeffective amount of a compound of Formula (I), a stereoisomeric formthereof and a pharmaceutically acceptable addition salt or solvatethereof, to warm-blooded animals, including humans.

Therefore, the invention also relates to a method for the preventionand/or treatment of any one of the diseases mentioned hereinbeforecomprising administering a therapeutically effective amount of compoundaccording to the invention to a patient in need thereof.

One skilled in the art will recognize that a therapeutically effectiveamount of the PAMs of the present invention is the amount sufficient tomodulate the activity of the mGluR2 and that this amount varies interalia, depending on the type of disease, the concentration of thecompound in the therapeutic formulation, and the condition of thepatient. Generally, an amount of PAM to be administered as a therapeuticagent for treating diseases in which modulation of the mGluR2 isbeneficial, such as the disorders described herein, will be determinedon a case by case by an attending physician.

Generally, a suitable dose is one that results in a concentration of thePAM at the treatment site in the range of 0.5 nM to 200 μM, and moreusually 5 nM to 50 μM. To obtain these treatment concentrations, apatient in need of treatment likely will be administered an effectivetherapeutic daily amount of about 0.01 mg/kg to about 50 mg/kg bodyweight, preferably from about 0.01 mg/kg to about 25 mg/kg body weight,more preferably from about 0.01 mg/kg to about 10 mg/kg body weight,more preferably from about 0.01 mg/kg to about 2.5 mg/kg body weight,even more preferably from about 0.05 mg/kg to about 1 mg/kg body weight,more preferably from about 0.1 to about 0.5 mg/kg body weight. Theamount of a compound according to the present invention, also referredto here as the active ingredient, which is required to achieve atherapeutically effect will, of course vary on case-by-case basis, varywith the particular compound, the route of administration, the age andcondition of the recipient, and the particular disorder or disease beingtreated. A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment the compounds according to the invention arepreferably formulated prior to admission. As described herein below,suitable pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients.

Because such positive allosteric modulators of mGluR2, includingcompounds of Formula (I), enhance the response of mGluR2 to glutamate,it is an advantage that the present methods utilize endogenousglutamate.

Because positive allosteric modulators of mGluR2, including compounds ofFormula (I), enhance the response of mGluR2 to agonists, it isunderstood that the present invention extends to the treatment ofneurological and psychiatric disorders associated with glutamatedysfunction by administering an effective amount of a positiveallosteric modulator of mGluR2, including compounds of Formula (I), incombination with an mGluR2 agonist. Examples of mGluR2 agonists include,for example, LY-379268; DCG-IV; LY-354740; LY-404039; LY-544344;LY-2140023; LY-181837; LY-389795; LY-446433; LY-450477; talaglumetad;MGS0028; MGS0039;(−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate;(+)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid;(+)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid;1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid; (+)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid;(+)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid;1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid;1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylicacid; or1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid. More preferable mGluR2 agonists include LY-379268; DCG-IV;LY-354740; LY-404039; LY-544344; or LY-2140023.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula (I) or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone.

Pharmaceutical Compositions

The present invention also provides compositions for preventing ortreating diseases in which modulation of the mGluR2 receptor isbeneficial, such as the disorders described herein. While it is possiblefor the active ingredient to be administered alone, it is preferable topresent it as a pharmaceutical composition. Accordingly, the presentinvention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to Formula (I), apharmaceutically acceptable salt thereof, a solvate thereof or astereochemically isomeric form thereof. The carrier or diluent must be“acceptable” in the sense of being compatible with the other ingredientsof the composition and not deleterious to the recipients thereof.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof, or anysubgroup or combination thereof may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18^(th) ed., Mack Publishing Company, 1990, see especiallyPart 8: Pharmaceutical preparations and their Manufacture). To preparethe pharmaceutical compositions of this invention, a therapeuticallyeffective amount of the particular compound, optionally in salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier or diluent, which carrier or diluentmay take a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, for oral,topical, rectal or percutaneous administration, by parenteral injectionor by inhalation. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as, for example, suspensions, syrups,elixirs, emulsions and solutions; or solid carriers such as, forexample, starches, sugars, kaolin, diluents, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of the ease in administration, oraladministration is preferred, and tablets and capsules represent the mostadvantageous oral dosage unit forms in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, surfactants, to aid solubility,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. Also included are solid form preparationsthat are intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, teaspoonfuls, tablespoonfuls, and segregated multiplesthereof.

Since the compounds according to the invention are orally administrablecompounds, pharmaceutical compositions comprising aid compounds for oraladministration are especially advantageous.

In order to enhance the solubility and/or the stability of the compoundsof Formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Alsoco-solvents such as alcohols may improve the solubility and/or thestability of the compounds according to the invention in pharmaceuticalcompositions.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% byweight, more preferably from 0.1 to 50% by weight of the activeingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9%by weight, more preferably from 50 to 99.9% by weight of apharmaceutically acceptable carrier, all percentages being based on thetotal weight of the composition.

As already mentioned, the invention also relates to a pharmaceuticalcomposition comprising the compounds according to the invention and oneor more other drugs for use as a medicament or for use in the treatment,prevention, control, amelioration, or reduction of risk of diseases orconditions for which compounds of Formula (I) or the other drugs mayhave utility. The use of such a composition for the manufacture of amedicament as well as the use of such a composition for the manufactureof a medicament in the treatment, prevention, control, amelioration orreduction of risk of diseases or conditions for which compounds ofFormula (I) or the other drugs may have utility are also contemplated.The present invention also relates to a combination of a compoundaccording to the present invention and an mGluR2 orthosteric agonist.The present invention also relates to such a combination for use as amedicine. The present invention also relates to a product comprising (a)a compound according to the present invention, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) a mGluR2orthosteric agonist, as a combined preparation for simultaneous,separate or sequential use in the treatment or prevention of a conditionin a mammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of mGluR2allosteric modulators, in particular positive mGluR2 allostericmodulators. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or diluents, or they may each be present in aseparate preparation together with pharmaceutically acceptable carriersor diluents.

The following examples are intended to illustrate but not to limit thescope of the present invention.

Chemistry

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification.

Hereinafter, “CI” means chemical ionisation; “DAD” means diode-arraydetector; “THF” means tetrahydrofuran; “DIPE” means diisopropylether;“DMF” means N,N-dimethylformamide; “EtOAc” means ethyl acetate; “DCM”means dichloromethane; “DCE” means dichloroethane; “BINAP” means1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-d]phenyl-phosphine]; “DBU”means 1,8-diaza-7-bicyclo[5.4.0]undecene; “DIPEA” meansN,N-diisopropylethylamine; “l” or “L” means liter; “LRMS” meanslow-resolution mass spectrometry/spectra; “HRMS” means high-resolutionmass spectra/spectrometry; “NH₄Ac” means ammonium acetate; “NH₄OH” meansammonium hydroxide; “NaHCO₃” means sodium hydrogencarbonate; “Et₂O”means diethyl ether; “MgSO₄” means magnesium sulphate; “EtOH” meansethanol; “ES” means electrospray; “Na₂SO₄” means sodium sulphate;“CH₃CN” means acetonitrile; “NaH” means sodium hydride; “MeOH” meansmethanol; “NH₃” means ammonia; “Na₂S₂O₃” means sodium thiosulphate;“AcOH” means acetic acid; “Et₃N” or “TEA” mean triethylamine; “NH₄Cl”means ammonium chloride; “K₂CO₃” means potassium carbonate; “Pd(PPh₃)₄”means tetrakis(triphenylphosphine)palladium(0); “eq” means equivalent;“S-Phos” means dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine;“X-Phos” means dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine; “r.t.” means room temperature;“mp” means melting point; “min” means minutes; “h” means hours; “s”means second(s); “TEA” means triethylamine; “TOF” means time of flight;“SFC” means supercritical fluid chromatography. Sep-Pak®Silica is acartridge with unbonded, highly-activated silica stationary phase;Amberlyst® 15 is a acidic cation exchange resin containing sulfonic acidgroups; H-Cube® is a continuous flow microfluidic hydrogenation reactor.

Microwave assisted reactions were performed in a single-mode reactor:Initiator™ Sixty EXP microwave reactor (Biotage AB), or in a multimodereactor: MicroSYNTH Labstation (Milestone, Inc.).

Thin layer chromatography (TLC) was carried out on silica gel 60 F254plates (Merck) using reagent grade solvents. Flash column chromatographywas performed on silica gel, particle size 60 Å, mesh=230-400 (Merck)using standard techniques. Automated flash column chromatography wasperformed using ready-to-connect cartridges from Merck, on irregularsilica gel, particle size 15-40 μm (normal phase disposable flashcolumns) on a SPOT or FLASH system from Armen Instrument.

Description 1 2,4-Dibromo-nicotinonitrile (D1)

To a solution of commercially available4-methoxy-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (95.47 g, 333 mmol)[C.A.S. 21642-98-8] in CH₃CN (670 ml), was added phosphorus(V)oxybromide(250 g, 166 mmol) portionwise. The resulting suspension was heated at60° C. for 16 h. After cooling to r.t., the reaction mixture was dilutedwith EtOAc and washed with water. The organic layer was separated andwashed with NaHCO₃ (aqueous sat. solution), dried (MgSO₄) andconcentrated in vacuo. The crude product thus obtained was trituratedwith diisopropyl ether to yield intermediate compound D1 (34.5 g, 79%)as a white solid.

GCMS (EI): MW (theor): 262; [M-2H⁺]: 260; RT (min): 9.67.

Description 2 4-Benzyloxy-2-bromo-nicotinonitrile (D2)

To a suspension of NaH (1.756 g, 45.818 mmol, mineral oil 60%) in DMF(200 ml) cooled at 0° C., was added benzyl alcohol (4.542 g, 42 mmol).The resulting mixture was stirred for 5 min. Then compound D1 (10 g,38.18 mmol) was quickly added. The resulting reaction mixture wasgradually warmed to r.t. and stirred for 1 h. The reaction mixture wasquenched with NH₄Cl (aqueous sat. solution), diluted with H₂O and theresulting mixture was extracted with Et₂O. The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by column chromatography (silica gel; DCM/7M solution ofNH₃ in MeOH up to 1% as eluent). The desired fractions were collectedand concentrated in vacuo to yield intermediate compound D2 (9.2 g,83%).

Description 3 4-Benzyloxy-2-hydrazino-nicotinonitrile (D3)

To a solution of compound D2 (1.2 g, 4.15 mmol) in THF (12 ml) was addedhydrazine monohydrate (0.416 g, 8.301 mmol). The reaction mixture washeated at 150° C. under microwave irradiation for 1 min. After cooling,additional hydrazine monohydrate (1 eq) was added to the reactionmixture, which was then heated at 150° C. under microwave irradiationfor 0.5 min. After cooling, the reaction mixture was concentrated invacuo. The residue thus obtained was triturated with Et₂O to yieldintermediate compound D3 (0.95 g, 95%).

Description 4N′-[3-cyano-4-(benzyloxy)pyridin-2-yl]-2-cyclopropylacetohydrazide (D4)

To a solution of D3 (4.099 g, 17.06 mmol) in dry DCM (112 ml) was addedEt₃N (2.76 g, 27.294 mmol) and cyclopropyl-acetyl chloride (3.438 g, 29mmol). The resulting reaction mixture was stirred at r.t. for 20 min.The mixture was concentrated in vacuo to yield compound D4 (5 g, 91%).

Description 57-Chloro-3-(cyclopropylmethyl)[1,2,4]triazolo[4,3-a]pyridine-8-carbonitrile(D5)

A solution of D4 (1.4 g, 4.343 mmol) and phosphorous(V)oxychloride(0.810 ml, 8.686 mmol) in DCE (15 ml) was heated at 150° C. undermicrowave irradiation for 5 min. After cooling, the mixture was dilutedwith DCM and washed with NaHCO₃ (aqueous sat. solution). The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM/7Msolution of NH₃ in MeOH up to 2% as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate compound D5(0.650 g, 64%).

Description 6 2-Bromo-3-cyano-4-(4-phenylpiperidinyl)pyridine (D6)

To a suspension of NaH (0.146 g, 3.818 mmol, 60%) in DMF (20 ml) cooledat 0° C. was added 4-phenylpiperidine (0.616 g, 3.818 mmol). Theresulting mixture was stirred for 5 min., then compound D1 (1 g, 3.016mmol) was added. The resulting reaction mixture was stirred for 1 h. Thereaction mixture was then quenched with NH₄Cl (aqueous sat. solution)and extracted with Et₂O. The organic layer was separated, dried (Na₂SO₄)and concentrated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/7M solution of NH₃ in MeOH gradient aseluent). The desired fractions were collected and concentrated in vacuoto yield intermediate compound D6 (0.985 g, 75%).

Description 7 [3-Cyano-4-(4-phenylpiperidinyl)pyridin-2-yl]-hydrazine(D7)

To a solution of compound D6 (0.5 mg, 1.461 mmol) in THF (4 ml), wasadded hydrazine monohydrate (0.366 g, 7.305 mmol). The reaction mixturewas heated at 160° C. under microwave irradiation for 15 min. Aftercooling, the resulting mixture was concentrated in vacuo. The residuethus obtained was purified by column chromatography (silica gel; DCM/7Msolution of NH₃ in MeOH up to 3% as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate compound D7(0.380 g, 89%) as a white solid.

Description 88-Cyano-7-(4-phenylpiperidinyl)[1,2,4]triazolo[4,3-a]pyridine (D8)

D7 (1 g, 3.409 mmol) and triethylorthoformate (7.577 g, 51.13 mmol) inxylene (25 ml) were heated in a sealed tube at 180° C. for 1 h. Aftercooling, the resulting mixture was concentrated in vacuo. The residuethus obtained was triturated with Et₂O to yield compound D8 (0.932 g,90%).

Description 9

8-Cyano-3-formyl-7(4-phenylpiperidinyl)[1,2,4]-triazolo[4,3-a]pyridine(D9)

D8 (0.25 g, 0.824 mmol) and phosphorus(V)oxychloride (0.116 ml, 1.236mmol) in DMF (5 ml) was heated in a sealed tube at 80° C. for 4 h. Aftercooling, the mixture was concentrated in vacuo. The crude product waspurified by column chromatography (silica gel; DCM/7M solution of NH₃ inMeOH up to 3% as eluent). The desired fractions were collected andconcentrated in vacuo to yield intermediate compound D9 (0.070 g, 26%).

Description 10 2,3-Dichloro-4-iodo-pyridine (D10)

To a solution of n-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) indry Et₂O (150 ml) cooled at −78° C., under a nitrogen atmosphere, wasadded 2,2,6,6-tetramethylpiperidine (11.64 ml, 69 mmol), dropwise. Theresulting reaction mixture was stirred at −78° C. for 10 min., and thena solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml)was added dropwise. The mixture was stirred at −78° C. for 30 min. andthen a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) wasadded. The mixture was allowed to warm to r.t. overnight, quenched withNa₂S₂O₃ (aqueous sat. solution) and extracted twice with EtOAc. Thecombined organic extracts were washed with NaHCO₃ (aqueous sat.solution), dried (Na₂SO₄) and concentrated in vacuo. The crude residuewas precipitated with heptane, filtered off and dried to yieldintermediate compound D10 (8.21 g, 44%) as a pale cream solid.

Description 11 (3-Chloro-4-iodo-pyridin-2-yl)hydrazine (D11)

To a solution of compound D10 (8 g, 29.21 mmol) in 1,4-dioxane (450 ml),was added hydrazine monohydrate (14.169 ml, 175.255 mmol). The reactionmixture was heated in a sealed tube at 70° C. for 16 h. After cooling,NH₄OH (32% aqueous solution) was added and the resulting mixture wasconcentrated in vacuo. The white solid residue thus obtained was takenup in EtOH. The suspension thus obtained was heated and then filteredoff and the filtered solution cooled to r.t. The precipitate formed wasfiltered off and then the filtrate concentrated in vacuo to yieldintermediate compound D11 (2.67 g, 52%) as a white solid.

Description 12N-(3-chloro-4-iodo-pyridin-2-yl)-2-cyclopropylacetohydrazide (D12)

To a solution of D11 (0.73 g, 2.709 mmol) in dry DCM (8 ml), cooled at0° C., was added Et₃N (0.562 ml, 4.064 mmol) and cyclopropyl-acetylchloride (0.385 g, 3.251 mmol). The resulting reaction mixture wasstirred at r.t. for 16 h and then NaHCO₃ (aqueous sat. solution) wasadded. The resulting solution was extracted with DCM. The organic layerwas separated, dried (MgSO₄) and concentrated in vacuo to yieldintermediate compound D12 (0.94 g, 99%).

Description 138-Chloro-3-cyclopropylmethyl-7-iodo[1,2,4]triazolo[4,3-a]pyridine (D13)

D12 (0.74 g, 2.389 mmol) was heated at 160° C. for 40 min. Aftercooling, the brown gum thus obtained was triturated with DIPE yieldingintermediate compound D13 (0.74 g, 93%).

Description 14 2,3-Dichloro-4-(4-phenyl-piperidin-1-yl)pyridine (D14)

A mixture of D10 (4 g, 14.605 mmol), 4-phenylpiperidine (3.532 g, 21.907mmol) and DIPEA (5.088 ml, 29.209 mmol) in CH₃CN (150 ml) was heated ina sealed tube at 110° C. for 16 h. The mixture was then treated withNaHCO₃ (aqueous sat. solution). The resulting mixture was extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄) and concentratedin vacuo. The crude product was purified by column chromatography(silica gel; DCM/7M solution of NH₃ in MeOH/EtOAc gradient as eluent).The desired fractions were collected and concentrated in vacuo to yieldintermediate compound D14 (2.32 g, 52%) as a white solid.

Description 15 3-chloro-2-hydrazino-4-(4-phenylpiperidin-1-yl)pyridine(D15)

To a suspension of compound D14 (0.25 g, 0.814 mmol) in 1,4-dioxane (3ml) was added hydrazine monohydrate (0.789 ml, 16.275 mmol). Thereaction mixture was heated at 160° C. under microwave irradiation for30 min. Then, after cooling, the solvent was evaporated in vacuo and theresidue obtained was taken up in DCM. The resulting solution was washedwith NaHCO₃ (aqueous sat. solution). The organic layer was separated,dried (MgSO₄) and concentrated in vacuo to yield intermediate compoundD15 (0.244 g, 99%).

Description 16N′-[3-chloro-4-(4-phenylpiperidin-1-yppyridin-2-yl]-3-methylbutanohydrazide(D16)

To a solution of D15 (0.6 g, 1.981 mmol) in dry DCE (10 ml) was addedEt₃N (0.442 ml, 3.17 mmol) and isovaleryl chloride [C.A.S. 108-12-3](0.311 ml, 2.576 mmol). The resulting reaction mixture was stirred atr.t. for 1 min. The mixture was concentrated in vacuo to yield compoundD16 (0.7 g, 91%).

Description 17N′-[3-chloro-4-(4-phenylpiperidin-1-yl)pyridine-2-yl]-2-ethoxyacetohydrazide(D17)

To a solution of D15 (0.497 g, 1.643 mmol) in dry DCM (10 ml) were addedEt₃N (0.366 ml, 2.629 mmol) and ethoxyacetyl chloride [C.A.S.14077-58-8] (0.282 g, 2.3 mmol). The resulting reaction mixture wasstirred at r.t. for 1 h. The mixture was then concentrated in vacuo toyield intermediate compound D17 (0.580 g, 91%).

Description 18 2,3-Dichloro-4-(4-fluoro-4-phenylpiperidin-1-yl)pyridine(D18)

A mixture of D10 (2 g, 7.302 mmol), 4-fluoro-4-phenylpiperidinehydrochloride (2.048 g, 9.493 mmol) [C.A.S. 1056382-25-2] and DIPEA(5.055 ml, 29.209 mmol) in CH₃CN (10 ml) was heated in a sealed tube at110° C. for 16 h. The mixture was then treated with NaHCO₃ (aqueous sat.solution). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel; Heptane/DCM from 4:1 up to 1:4 as eluent).The desired fractions were collected and concentrated in vacuo to yieldintermediate compound D18 (0.88 g, 37%) as a white solid.

Description 193-Chloro-4-(4-fluoro-4-phenylpiperidin-1-yl)-2-hydrazinopiridine (D19)

To a suspension of compound D18 (0.966 g, 2.97 mmol) in EtOH (6 ml), wasadded hydrazine monohydrate (2.882 ml, 59.407 mmol). The reactionmixture was heated under microwave irradiation at 160° C. for 20 min.After cooling, the solvent was evaporated in vacuo and the residue thusobtained was taken up in DCM. The resulting solution was washed withNaHCO₃ (aqueous sat. solution). The organic layer was separated, dried(MgSO₄) and concentrated in vacuo. The residue thus obtained wastriturated with Et₂O to yield intermediate compound D19 (0.8 g, 84%) asa white solid.

Description 20

N′-[3-chloro-4-(4-fluoro-4-phenylpiperidin-1-yl)pyridin-2-yl]-3,3,3-trifluoropropanohydrazide(D₂₀)

To a solution of D19 (2.040 g, 6.359 mmol) in dry DCM (30 ml) cooled at0° C., were added Et₃N (1.418 ml, 10.175 mmol) and3,3,3-trifluoropropionyl chloride [C.A.S. 41463-83-6] (1.035 ml, 8.267mmol). The resulting reaction mixture was gradually warmed to r.t. andstirred for 1 h. NaHCO₃ (aqueous sat. solution) was added and theresulting solution was then extracted with DCM. The organic layer wasseparated, dried (MgSO₄) and concentrated in vacuo to yield intermediatecompound D₂₀ (2.72 g, 99%).

Description 21

l′-(2,3-dichloropyridin-4-yl)-3H-spiro[2-benzofuran-1,4′-piperidine](D21)

A mixture of D10 (1 g, 3.655 mmol),spiro[isobenzofuran-1(3H),4′-piperidine], hydrochloride [CAS 37663-44-8](0.83 g, 4.386 mmol) and DIPEA (1.273 ml, 7.309 mmol) in CH₃CN (9 ml)was heated in a sealed tube at 110° C. for 16 h. The mixture was thentreated with NaHCO₃ (aqueous sat. solution) and extrated with EtOAc. Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by column chromatography (silica gel;DCM/EtOAc up to 2% as eluent). The desired fractions were collected andconcentrated in vacuo to yield intermediate compound D21 (0.199 g, 16%)as a white solid. M.P. 160.8° C.

Description 221′-(3-chloro-2-hydrazinopyridin-4-yl)-3H-spiro[2-benzofuran-1,4′-piperidine](D22)

To a suspension of compound D21 (0.199 g, 0.594 mmol) in EtOH (4 ml),was added hydrazine monohydrate (0.588 ml, 11.872 mmol). The reactionmixture was heated at 160° C. under microwave irradiation for 20 min.Then, additional hydrazine monohydrate (20 eq) was added to the reactionmixture, which was then subjected to microwave irradiation at 170° C.for 30 min. Upon cooling, a precipitate developed, which was filteredoff and NaHCO₃ (aqueous sat. solution) was added to the filtrate. Theresulting solution was extracted with DCM. The organic layer wasseparated, dried (MgSO₄) and concentrated in vacuo to yield intermediatecompound D22 (0.177 g, 90%).

Description 23N′-[3-chloro-4-(1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl)pyridin-2-yl]-2,2,2-trifluoroacetohydrazide(D23)

To a solution of D22 (0.177 g, 0.535 mmol) in dry DCM (3 ml) cooled at0° C. was added Et₃N (0.112 g, 0.803 mmol) and 3,3,3-trifluoropropionylchloride [C.A.S. 41463-83-6] (0.087 ml, 0.696 mmol). The resultingreaction mixture was gradually warmed to r.t. and stirred for 2 h. Themixture was concentrated in vacuo. The residue thus obtained wastriturated with Et₂O to yield intermediate compound D23 (0.369 g) as acrude material, which was used without further purification.

Description 24 2,4-Dichloro-3-iodo-pyridine (D24)

To a solution of 2,4-dichloropyridine (5.2 g, 35.137 mmol) anddiisopropylamine (3.911 g, 38.651 mmol) in dry THF (40 ml) cooled at−78° C. under a nitrogen atmosphere, was added n-butyllithium (24.157ml, 38.651 mmol, 1.6 M in hexanes) dropwise. The resulting reactionmixture was stirred at −78° C. for 45 min. and then a solution of iodine(9.81 g, 38.651 mmol) in dry THF (20 ml) was added dropwise. The mixturewas stirred at −78° C. for 1 h., allowed to warm to r.t., diluted withEtOAc and quenched with NH₄Cl (aqueous sat. solution) and Na₂S₂O₃(aqueous sat. solution). The organic layer was separated, washed withNaHCO₃ (aqueous sat. solution), dried (Na₂SO₄) and concentrated invacuo. The crude product was purified by column chromatography (silicagel; Heptane/DCM up to 20% as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate compound D24(7.8 g, 81%).

Description 25 2,4-Dichloro-3-trifluoromethyl-pyridine (D25)

To a mixture of compound D24 (2 g, 7.302 mmol) in DMF (50 ml) were addedfluorosulfonyl-difluoro-acetic acid methyl ester [C.A.S. 680-15-9](1.858 ml, 14.605 mmol) and copper(I)iodine (2.796. g, 14.605 mmol). Thereaction mixture was heated in a sealed tube at 100° C. for 5 h. Aftercooling, the solvent was evaporated in vacuo. The crude product waspurified by column chromatography (silica gel; DCM as eluent). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate compound D25 (1.5 g, 95%).

Description 26 4-Benzyloxy-2-chloro-3-trifluoromethyl-pyridine (D26)

To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF(50 ml) cooled at 0° C., was added benzyl alcohol (1.262 ml, 12.2 mmol).The resulting mixture was stirred for 2 min., then, intermediatecompound D25 (2.5 g, 11.575 mmol) was added. The resulting reactionmixture was gradually warmed to r.t. and stirred for 1 h.

The reaction mixture was quenched with water and extracted with Et₂O.The organic layer was separated, dried (Na₂SO₄) and concentrated invacuo. The crude product was purified by column chromatography (silicagel; Heptane/DCM gradient as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate compound D26(1.1 g, 33%).

Description 27 4-(benzyloxy)-2-hydrazino-3-(trifluoromethyl)pyridine(D27)

To a suspension of compound D26 (1.09 g g, 3.789 mmol) in 1,4-dioxane (9ml), was added hydrazine monohydrate (3.676 ml, 75.78 mmol). Thereaction mixture was heated at 160° C. under microwave irradiation for30 min. After cooling, the resulting solution was concentrated in vacuo.The residue thus obtained was dissolved in DCM and washed with NaHCO₃(aqueous sat. solution). The organic layer was separated, dried (Na₂SO₄)and concentrated in vacuo to yield intermediate compound D27 (0.890 g,83%) as a white solid.

Description 28N′-[4-(benzyloxy)-3-(trifluoromethyl)pyridin-2-yl]-2-cyclopropylacetohydrazide(D28)

To a solution of D27 (0.890 g, 3.142 mmol) in dry DCM (3 ml) was addedEt₃N (0.653 ml, 4.713 mmol) and cyclopropyl-acetyl chloride [C.A.S.543222-65-5] (0.373 g, 3.142 mmol). The resulting reaction mixture wasstirred at 0° C. for 20 min. The resulting mixture was then concentratedin vacuo to yield intermediate compound D28 (1.1 g, 96%).

Description 297-Chloro-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D29)

D28 (1.14 g, 1.872 mmol) and phosphorous(V)oxychloride (0.349 g, 3.744mmol) in CH₃CN (10 ml) were heated at 150° C. under microwaveirradiation for 10 min. After cooling, the resulting reaction mixturewas diluted with DCM and washed with NaHCO₃ (aqueous sat. solution),dried (Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby column chromatography (silica gel; DCM/7M solution of NH₃ in MeOH upto 20% as eluent). The desired fractions were collected and concentratedin vacuo to yield intermediate compound D29 (0.261 g, 51%) as a whitesolid.

Description 302-Chloro-3-trifluoromethyl-4-(4-Fluoro-4-phenylpiperidinyl)-pyridine(D30)

D25 (0.4 g, 1.852 mmol), 4-fluoro-4-phenylpiperidine hydrochloride[C.A.S. 1056382-25-2] (0.399 g, 1.852 mmol) and N,N-DIPEA (0.645 ml,3.704 mmol) in CH₃CN (4 ml) were heated in a sealed tube at 110° C. for4 h. The mixture was diluted with EtOAc and washed with NaHCO₃ (aqueoussat. solution). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate compound D30(0.53 g, 62%).

Description 314-(4-fluoro-4-phenylpiperidin-1-yl)-2-hydrazino-3-(trifluoromethyl)pyridine(D31)

To a suspension of compound D30 (0.530 g, 1.152 mmol) in THF (10 ml),was added hydrazine monohydrate (0.224 ml, 4.61 mmol). The reactionmixture was heated at 160° C. under microwave irradiation for 45 min.After cooling, the resulting solution was concentrated in vacuo. Theresidue thus obtained was triturated with Et₂O to yield intermediatecompound D31 (0.280 g, 69%) as a white solid.

Description 322-cyclopropyl-N′-[4-(4-fluoro-4-phenylpiperidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl]acetohydrazide(D32)

To a solution of D31 (0.29 g, 0.818 mmol) in dry DCM (10 ml) was addedEt₃N (0.201 ml, 1.473 mmol) and cyclopropyl-acetyl chloride [C.A.S.543222-65-5] (0.116 g, 0.982 mmol). The resulting reaction mixture wasstirred at r.t. for 20 min. The mixture was then concentrated in vacuoto yield intermediate compound D32 (0.354 g, 99%).

Description 332-Chloro-3-trifluoromethyl-4-(4-phenylpiperidin-1-yl)-pyridine (D33)

To a solution of NaH (0.193 g, 4.834 mmol) in DMF (20 ml) cooled at 0°C., was added 4-phenylpiperidine (0.844 g, 5.236 mmol) was added. Theresulting reaction mixture was stirred at 0° C. for 10 min., before D25(0.87 g, 4.028 mmol) was added. The resulting mixture was warmed to r.t.and stirred for 1 h. The mixture was then quenched with water andextracted with Et₂O. The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/7M solution of NH₃ in MeOH up to 2% aseluent). The desired fractions were collected and concentrated in vacuoto yield intermediate compound D33 (0.73 g, 53%).

Description 34[2-Hydrazino-4-(4-phenylpiperidin-1-yl)-3-(trifluoromethyl)pyridine(D34)

To a suspension of compound D33 (0.350 g, 1.027 mmol) in THF (6 ml), wasadded hydrazine monohydrate (0.199 ml, 4.108 mmol). The reaction mixturewas heated at 160° C. under microwave irradiation for 45 min. Additionof hydrazine monohydrate (0.199 and 0.249 ml) to the reaction mixturefollowed by heating at 160° C. under microwave irradiation for 45 minwas repeated twice. After cooling, the resulting solution wasconcentrated in vacuo and the residue thus obtained was triturated withEt₂O to yield intermediate compound D34 (0.320 g, 93%) as a white solid.

Description 35N-[4-(4-phenylpiperidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl]pentanehydrazide(D35)

To a solution of D34 (0.350 g, 1.041 mmol) in dry DCM (10 ml) was addedEt₃N (0.255 ml, 1.873 mmol) and pentanoyl chloride [C.A.S. 638-29-9](0.126 ml, 1.041 mmol). The resulting reaction mixture was stirred atr.t. for 10 min. The mixture was then concentrated in vacuo to yieldintermediate compound D35 (0.435 g, 99%).

Description 36 2,3-Dichloro-pyridine-4-carbaldehyde (D36) [C.A.S.884495-41-4]

To a solution of 2,3-dichloropyridine [C.A.S. 2402-77-9] (10 g, 67.57mmol) in dry THF (200 ml) cooled at −78° C. under a nitrogen atmosphere,was added dropwise n-butyllithium (37.165 ml, 74 mmol, 2 M in hexanes).The resulting reaction mixture was stirred at −78° C. for 20 min. Thendry DMF (6.28 ml, 81.087 mmol) was added dropwise. After 15 min.stirring at −78° C., the mixture was allowed to warm to r.t., quenchedwith water and extracted with DCM. The combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo. The crude residue was purifiedby short open column chromatography (DCM as eluent). The desired productfractions were collected and concentrated in vacuo to give a residuethat was further purified by column chromatography (silica gel;DCM/heptane up to 50% as eluent). The desired fractions were collectedand concentrated in vacuo to yield intermediate compound D36 (4.15 g,34.9%) as a white solid.

Description 37 2,3-Dichloro-4-[(4-phenyl-piperidin-1-yl)methyl]pyridine(D37)

To a solution of 4-phenylpiperidine [CAS 771-99-3] (0.155 g, 0.818 mmol)in DCE (27 ml) was added D36 (1 g, 5.68 mmol), sodiumtriacetoxy-borohydride (1.325 g, 6.25 mmol) and acetic acid (0.53 ml)and the resulting mixture was stirred at r.t. for 1 day. The reactionmixture was neutralized with NaHCO₃ (aqueous sat. solution) andextracted with DCM. The organic layer was dried (MgSO₄) and concentratedin vacuo. The crude product thus obtained was purified by columnchromatography (silica gel; DCM/MeOH up to 3% as eluent). The desiredfractions were collected and concentrated in vacuo to yield intermediatecompound D37 (0.582 g, 31.9%) as a white solid.

Description 383-Chloro-2-hydrazino-[4-(4-phenylpiperidin-1-yl)methyl]pyridine (D38)

To a suspension of compound D37 (0.521 g, 1.622 mmol) in EtOH (6 ml),was added hydrazine monohydrate (1.574 ml, 32.448 mmol). The reactionmixture was heated at 160° C. under microwave irradiation for 20 min.After cooling, a white solid precipitated out. The solid was washed withEt₂O and dissolved in a DCM-7M solution of NH₃ in MeOH mixture. Theresulting solution was washed with NaHCO₃ (aqueous sat. solution). Theorganic layer was separated, dried (MgSO₄) and concentrated in vacuo toyield intermediate compound D38 (0.452 g, 88%) as a white solid.

Description 39N′-{3-chloro-4-[(4-phenylpiperidin-1-yl)methyl]pyridin-2-yl}-2-cyclopropylacetohydrazide(D39)

To a solution of D38 (0.179 g, 0.565 mmol) in dry DCM (3 ml) cooled at0° C. were added Et₃N (0.118 ml, 0.847 mmol) and cyclopropyl-acetylchloride [C.A.S. 543222-65-5] (0.080 g, 0.678 mmol). The resultingreaction mixture was gradually warmed to r.t. and stirred for 2 h. Themixture was concentrated in vacuo to yield intermediate compound D39(0.269 g) as a crude material, which was used without furtherpurification.

Description 40 tert-butyl 4-[2-(1-hydroxy-1-methylethyl)phenyl]piperidine-1-carboxylate (D40)

To a solution of 4-[2-(methoxycarbonyl)phenyl]-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester [C.A.S. 732275-95-5] (2.6 g, 8.14 mmol) inTHF (150 ml) cooled at 0° C. under a nitrogen atmosphere, was addedmethylmagnesium bromide—1.4 M solution in toluene/THF (17.443 ml, 24.421mmol), dropwise and the resulting reaction mixture was stirred at 45° C.for 2 h. After cooling in an ice bath the mixture was carefully quenchedwith NH₄Cl (saturated aqueous sat. solution) and then extracted withEtOAc. The combined organic phase was dried (Na₂SO₄) and the solventevaporated in vacuo to yield D40 (2.77 g, 69%).

Description 41 2-(2-Piperidin-4-ylphenyl)propan-2-ol (D41)

A solution of intermediate D40 (27 g, 5.636 mmol) and KOH (2.433 g,43.357 mmol) in isopropyl alcohol (13.5 ml) and water (27 ml) was heatedat 180° C. under microwave irradiation for 60 min. After cooling tor.t., the mixture was washed with water and NaCl (aqueous saturatedsolution). The organic phase was dried (Na₂SO₄) and the solventevaporated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/7M solution of NH₃ in MeOH up to 10% aseluent). The desired fractions were collected and concentrated in vacuoto yield intermediate compound D41 as a yellow solid (1.041. g, 84%).M.P. 219.5° C.

Description 42 2-Cyano-4,4,4-trifluoro-3-phenyl-but-2-enoic acid ethylester (D42)

A mixture of trifluoromethylphenylketone [C.A.S. 434-45-7] (5 g, 28.71mmol) and ethyl cyanoacetate [C.A.S. 105-56-6] (3.61 mL, 31.58 mmol) inDCM (100 mL) was flushed with nitrogen, then cooled to 0° C. andmaintained under a nitrogen atmosphere. Neat titanium(IV) chloride (6.79mL, 60.30 mmol) was added dropwise, the reaction mixture was stirred for10 min at 0° C. and then pyridine (1.5 mL) was added dropwise. When theaddition was complete, the ice bath was removed, the reaction reactionwas stirred for 30 min at r.t., additional pyridine was added (5 mL) andthe reaction mixture was stirred for a further 20 h at r.t. The mixturewas then diluted in DCM (100 mL) and washed with HCl 2N (2×200 mL),water (300 mL) and brine (100 mL). The organic phase was evaporated toyield intermediate compound D42 (4.8 g, 61%) as a mixture of E/Zisomers, as a colourless oil which was used without furtherpurification.

Description 432,6-Dioxo-4-phenyl-4-trifluoromethyl-piperidine-3,5-dicarbonitrile (D43)

To a solution of intermediate D42 (mixture of isomers) (4.71 g, 17.4mmol) and 2-cyanoacetamide [C.A.S. 107-91-5] (2.51 g, 29.94 mmol), indry EtOH (150 mL), was added a solution of sodium acetate (59.89 mmol)in EtOH, and the reaction mixture was stirred for 46 h at r.t. Thesolvent was evaporated and the residue was treated with water (60 mL),the resulting aqueous solution was neutralized with HCl 1N to pH 3,extracted with EtOAc (3×100 mL) and the organic phase was dried overMgSO₄ and evaporated to give intermediate D43 (4.71 g, 87%) as a brownoil which was used without further purification.

Description 449-Phenyl-9-trifluoromethyl-3,7-diaza-bicyclo[3.3.1]nonane-2,4,6,8-tetraone(D43)

To a mixture of intermediate D43 (4.71 g, 15.33 mmol) in AcOH (25 mL)and water (25 mL) was added concentrated sulfuric acid (25 g) and thereaction was heated at reflux for 20 h (bath temperature 170° C.). Thereaction mixture was cooled to 0° C. and 30 mL of water were added. Asolid precipitated that was filtered off and was washed with cold waterto yield intermediate D44 (3.6 g, 71%) as a cream solid that was usedwithout further purification.

Description 45 3-Phenyl-3-trifluoromethyl-pentanedioic acid (D45)

To 20 mL of an aqueous solution of KOH (20%) was added intermediatecompound D44 (2.6 g, 7.96 mmol) and the reaction mixture was heated atreflux for 3 h. The reaction mixture was then cooled to 0° C. and asolution of concentrated sulfuric acid (7 g) in water (20 mL) was addedcarefully. The resulting mixture was heated at reflux for 2 h, thencooled to r.t. and extracted with EtOAc (3×50 mL). The organic phase wasevaporated in vacuo to yield afford D45 (1.81 g, 81%) as a yellowishoil.

Description 46 4-Phenyl-4-trifluoromethyl-piperidine-2,6-dione (46)

A mixture of intermediate D45 (1.8 g, 6.51 mmol) in acetic anhydride(16.6 g) was heated at reflux (bath temperature 180° C.) for 2 h. Theexcess acetic anhydride was removed by evaporation, urea (0.42 g, 6.51mmol) was added to the resulting residue and heated at 195° C. for 15min. The resulting mixture was cooled and the crude was purified bycolumn chromatography (DCM/MeOH 9.5/0.5) to afford intermediate D46 (1.5g, 89%) as a white solid.

Description 47 4-Phenyl-4-trifluoromethyl-piperidine (D47)

To a mixture of intermediate D46 (1.6 g, 6.22 mmol) in dry THF (150 mL),was added BH₃-THF (21.77 mL, 1M) at r.t. and the reaction was heated atreflux for 20 h. The reaction mixture was cooled to r.t. and quenched bythe careful addition of 6 N HCl (10 mL). After the gas evolution ceased,the mixture was concentrated under reduced pressure and the residue thusobtained was treated with additional 6 N HCl (70 mL). The mixture washeated at reflux for 1 hour, then cooled to r.t. and treated with a 2Msolution of NaOH to pH 11. The crude was extracted with DCM (3×30 mL) toafford a transparent oil, which was purified by column chromatography(DCM/MeOH (1% NH₃) 9/1) to yield intermediate D47 (0.91 g, 64%) as acolorless oil which crystallized upon standing. M.P.=87.6° C. ¹H NMR(400 MHz, CDCl₃) δ ppm 2.01-2.12 (m, 2H), 2.15 (br. s., 1H), 2.47 (dd,J=14.1, 2.3 Hz, 2H), 2.63 (br t, J=12.5 Hz, 2H), 3.00 (br d, J=12.7 Hz,2H), 7.31-7.37 (m, 1H), 7.38-7.49 (m, 4H).

Description 481′-(2,3-Dichloropyridin-4-yl)spiro[1-benzofuran-3,4′-piperidine] (D48)

A mixture of intermediate D10 (3 g, 10.953 mmol),4-spiro-[3-(2,3-dihydro-benzofuran)]piperidine [CAS 171-77-7] (2.28 g,12.049 mmoland DIPEA (7.63 ml, 43.814 mmol) in CH₃CN (100 ml) was heatedin a sealed tube at 110° C. for 3 days. The mixture was then treatedwith NaHCO₃ (aqueous sat. solution) and extracted with EtOAc. Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by column chromatography (silica gel;DCM/7M solution of NH₃ in MeOH up to 4% as eluent), the desiredfractions were collected and concentrated in vacuo to yield intermediateD48 (2.9 g, 63%) as a white solid. M.P. 177.2° C.

Description 491′-(3-Chloro-2-hydrazinopyridin-4-yl)spiro-[1-benzofuran-3,4′-piperidine](D49)

To a suspension of intermediate D48 (1.13 g, 3.371 mmol) in EtOH (11.3ml), was added hydrazine monohydrate (0.588 ml, 11.872 mmol). Thereaction mixture was heated at 160° C. under microwave irradiation for50 min. Additional hydrazine monohydrate (5 eq) was added to thereaction mixture, which was then heated at 160° C. for 35 min undermicrowave irradiation. The reaction mixture was diluted with DCM andwashed with NaHCO₃ (aqueous sat. solution). The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo to yieldintermediate D49 (1.05 g, 94%) which was used without furtherpurification.

Description 50N′-[3-chloro-4-(1′H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl)pyridin-2-yl]-3,3,3-trifluoropropanehydrazide(D49)

To a solution of intermediate D49 (1.05 g, 3.174 mmol) in dry DCM (100ml) cooled at 0° C. was added Et₃N (0.792 ml, 5.713 mmol) and3,3,3-trifluoropropionyl chloride [C.A.S. 41463-83-6] (0.465 mg, 3.174mmol). The resulting reaction mixture was gradually warmed to r.t. andstirred for 1 h. The mixture was concentrated in vacuo and the residuethus obtained was triturated with Et₂O to yield intermediate D50 (1.39g) as a crude material, which was used without further purification.

Description 51N′-[4-(4-fluoro-4-phenylpiperidin-1-yl)-3-(trifluoromethyl)pyridine-2-yl]-2-(1-methylethoxy)acetohydrazide(D51)

To a solution of intermediate D31 (0.29 g, 0.818 mmol),2-isopropoxyacetic acid [C.A.S. 33445-07-7] (0.116 g, 0.982 mmol) and1-hydroxybenzotriazole (0.167 g, 1.233 mmol) in dry THF (3.5 ml) wasadded N,N′-dicyclohexylcarbodiimide (0.254 g, 1.233 mmol) in dry DCM (14ml). The resulting reaction mixture was stirred at r.t. for 16 h. Theresulting solution was washed with NaHCO₃ (aqueous sat. solution). Theorganic layer was separated, dried (MgSO₄) and concentrated in vacuo.The crude product was purified by column chromatography (silica gel;DCM/EtOAc gradient as eluent). The desired fractions were collected andconcentrated in vacuo. The solid obtained was triturated with DCM. Thesoluble fraction was collected and concentrated in vacuo to yieldintermediate D51 (0.245 g, 52%).

Description 524-(3,6-Difluoro-2-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (D52)

2-Bromo-1,4-difluoro-3-methoxy-benzene (0.7 g, 3.139 mmol) [C.A.S.1208076-11-2] was added to a stirred solution of3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1(2H)-pyridinecarboxylicacid, 1,1-dimethylethyl ester (1.262 g, 4.08 mmol) [C.A.S. 286961-14-6],Pd(PPh₃)₄ (0.072 g, 0.062 mmol) and K₂CO₃ (3.5 ml, aqueous sat.solution) in 1,4-dioxane (7 ml). The reaction mixture was heated at 150°C. under microwave irradiation for 10 min. After cooling, the mixturewas diluted with water and extracted with Et₂O. The organic phase wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by column chromatography (silica gel; Heptane/EtOAc 90/10to 80/2 as eluent). The desired fractions were collected andconcentrated in vacuo to give a residue that was triturated with Et₂O toyield intermediate D52 (0.233 g, 22%). Description 534-(3,6-Difluoro-2-methoxy-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (D53)

A solution of intermediate D52 (0.233 g, 0.716 mmol) in EtOH (15 ml) washydrogenated in a H-Cube® reactor (1 ml/min, Pd(OH)₂ 20% cartridge, fullH₂ mode, 80° C.). The solvent was concentrated in vacuo to yieldintermediate D53 (0.197 g, 84%).

Description 54 4-(3,6-Difluoro-2-methoxy-phenyl)-piperidine (D54)

Hydrochloric acid (7M in isopropanol) (2 ml) was added to a stirredsolution of intermediate D53 (0.197 g, 0.602 mmol) in MeOH (1 ml). Themixture was stirred at r.t. for 1.5 h. The mixture was diluted withNa₂CO₃ (aqueous saturated solution) and extracted with DCM. The organicphase was separated, dried (Na₂SO₄) and concentrated in vacuo to yieldintermediate D54 (0.117 g, 85%).

Description 554-(2,3-Dichloro-pyridin-4-yl)-2,2-dimethyl-1-phenyl-piperazine (D55)

A mixture of D10 (1.083 g, 3.955 mmol), 2,2-dimethyl-1-phenylpiperazine(0.903 g, 4.745 mmol) [C.A.S. 2946-75-0] and DIPEA (1.378 ml, 7.909mmol) in CH₃CN (15 ml) was heated in a sealed tube at 100° C. for 5days. After cooling, the solvent was concentrated in vacuo. The residuewas purified by column chromatography (silica gel; Heptane/EtOAc 100/10to 80/20 as eluent). The desired fractions were collected andconcentrated in vacuo to yield intermediate D55 (0.56 g, 42%).

Description 56[3-Chloro-4-(3,3-dimethyl-4-phenyl-piperazin-1-yl)-pyridin-2-yl]-hydrazine(D56)

To a suspension of D55 (0.56 g, 1.665 mmol) in DMSO (6 ml) was addedhydrazine monohydrate (1.649 ml, 33.307 mmol). The reaction mixture washeated at 110° C. overnight. Then, after cooling, the mixture wasdiluted with NaHCO₃ (aqueous saturated solution) and extracted withEtOAc. The organic phase was separated, dried (Na₂SO₄) and concentratedin vacuo. The residue was lyophilized to yield intermediate D56 (0.371g, 67%).

Description 57N′-[3-chloro-4-((3,3-dimethyl-4-phenyl-piperazin-1-yl)pyridin-2-yl]-3,3,3-trifluoropropanohydrazide(D57)

To a solution of D56 (0.371 g, 1.12 mmol) and Et₃N (0.116 ml, 0.877mmol) in dry DCM (17 ml) cooled at 0° C., was added a solution of3,3,3-trifluoropropionyl chloride [C.A.S. 41463-83-6] (0.82 ml, 0.56mmol) in dry DCM (3 ml). The resulting reaction mixture was graduallywarmed to r.t. and stirred for 1 h. The reaction mixture was cooled at0° C. and additional Et₃N (0.29 mmol) and 3,3,3-trifluoropropionylchloride (0.25 mmol) were added. The resulting reaction mixture wasgradually warmed to r.t. and stirred for an additional 1 h. NaHCO₃(aqueous sat. solution) was added and the resulting solution was thenextracted with DCM. The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo to yield intermediate D57 (0.459 g, 92%).

Description 582-(1-Benzyl-1,2,3,6-tetrahydro-pyridin-4-ylmethoxy)-3-bromo-pyridine(D58)

To a solution of (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol(0.675 g, 3.019 mmol) [C.A.S. 158984-76-0] in dry THF (40 ml) cooled at0° C., was added NaH (0.138 g, 3.622 mmol; 60% mineral oil). Theresulting reaction mixture was stirred at 0° C. for 30 min. Then, asolution of 2-chloro-3-bromopyridine (0.58 g, 3.019 mmol) in dry THF (10ml) was added and the mixture was heated in a sealed tube at 85° C. for2 h. After cooling, additional(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.675 g, 3.019mmol), NaH (0.138 g, 3.622 mmol; 60% mineral oil) were added to thereaction mixture, which was then heated at 85° C. overnight. Then, aftercooling, the mixture was diluted with water and extracted with EtOAc.The organic phase was separated, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by column chromatography (silica gel;DCM/7M solution of NH₃ in MeOH up to 2% as eluent). The desiredfractions were collected and concentrated in vacuo to yield intermediateD58 (0.55 g, 50%).

Description 59 1-Benzyl-spiro[furo[2,3-b]pyridine-3(2H),4′-piperidine](D59)

A solution of D58 (1.12 g, 3.117 mmol), tributyltin hydride (0.963 ml,3.585 mmol) and α,α′-azodiisobutyronitrile (0.512 mg, 3.117 mmol) in drytoluene (65 ml) was heated in a sealed tube at 135° C. for 20 h. Themixture was concentrated in vacuo. The residue was purified by columnchromatography (silica gel; DCM/7M solution of NH₃ in MeOH up to 3% aseluent). The desired fractions were collected and concentrated in vacuo.The residue was dissolved in MeOH and Amberlyst® 15 ion exchange resin(3.678 g) was added. The resulting mixture was shaken at r.t. for 16 h.The resin was filtered off, washed with MeOH and DCM, and dried invacuo. The resin was suspended in NH₃ (7M in MeOH) and shaken at r.t.for 2 h. The resin was filtered off and the filtrate was concentrated invacuo. The crude residue was dissolved in DCM (50 ml) and KF (50 ml ofaqueous saturated solution) was added. The mixture was stirred at r.t.for 1 h. The organic phase was separated, washed with KF (aqueous sat.solution), NaCl (aqueous sat. solution), dried (Na₂SO₄) and concentratedin vacuo. The residue was triturated with heptane to give intermediateD59 (0.45 g, 51%) as a pale yellow solid.

Description 60 Spiro[furo[2,3-b]pyridine-3(2H),4′-piperidine] (D60)

To a stirred solution of D59 (1.6 g, 5.707 mmol) and Et₃N (0.793 ml,5.707 mmol) in DCM (32 ml) cooled at 0° C. was added dropwiseα-chloroethoxycarbonyl chloride (1.246 ml, 11.414 mmol). The mixture wasstirred at 0° C. for 1 min, then, the crude was concentrated in vacuo.The residue was dissolved in MeOH (32 ml), heated at reflux for 1 h andconcentrated in vacuo. The residue was suspended in n-butanol andstirred at r.t. overnight. The solid was filtered off and washed withn-butanol and the filtrate was concentrated in vacuo. The residue wasdissolved in MeOH and Amberlyst® 15 ionexchange resin (2.78 g) wasadded. The resulting mixture was shaken at r.t. for 16 h. The resin wasfiltered off, washed with MeOH and DCM, and dried in vacuo. The resinwas suspended in NH₃ (7M in MeOH) and shaken at r.t. for 2 h The resinwas filtered off, washed with NH₃ (7M in MeOH) and the filtrate wasconcentrated in vacuo to give intermediate D60 (0.688 g, 63%) as a brownoil.

Description 61 4-Phenyl-4,7-diaza-spiro[2.5]octane-7-carboxylic acidtert-butyl ester (D61)

A stirred solution of 4,7-diaza-spiro[2.5]octane-7-carboxylic acidtert-butyl ester (0.1 g, 0.471 mmol) [C.A.S. 886766-28-5], iodobenzene(0.026 ml, 0.236) and CsOH (0.079 g, 0.471 mmol) in DMSO (1 ml) washeated in a sealed tube at 120° C. for 20 min. After cooling, additional4,7-diaza-spiro[2.5]octane-7-carboxylic acid tert-butyl ester (2 eq.)was added, and the mixture was then heated at 120° C. for 20 min. Themixture was cooled. The mixture was washed with NH₄Cl (aqueous sat.solution) was added and extracted with Et₂O. The organic phase wasseparated, washed with water, dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by manifold (Sep-Pak® silica cartridge;DCM as eluent). The desired fractions were collected and concentrated invacuo to yield intermediate D61 (0.021 g, 31%) as a white solid.

Description 62 4-Phenyl-4,7-diaza-spiro[2.5]octane (D62)

To a stirred solution of D61 (0.466 g, 1.616 mmol) in dry DCM (8.5 ml)was added, trifluoroacetic acid (1.4 ml). The mixture was stirred atr.t. overnight then concentrated in vacuo. The residue was treated withwater and extracted with DCM. The aqueous phase was collected, basifiedwith NaOH 50% (aqueous solution) and extracted with DCM. The organicphase was separated, dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by manifold (Sep-Pak® silica cartridge; DCM/7Msolution of NH₃ in MeOH up to 2% as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate D62 (0.101 g,33%).

Description 63N′-[4-(benzyloxy)-3-(trifluoromethyl)pyridin-2-yl]-2-cyclopropylpropionicacid hydrazide (D63)

To a solution of D27 (1.851 g, 6.536 mmol) in dry DCM (40 ml) was addedEt₃N (3.617 ml, 26.146 mmol) and cyclopropyl-propionyl chloride [C.A.S.56105-20-5] (1.04 g, 7.844 mmol). The resulting reaction mixture wasstirred at r.t. for 1 h. The mixture was washed with NaHCO₃ (aqueoussat. solution). The organic phase was separated, dried (Na₂SO₄) andconcentrated in vacuo to yield intermediate D63 (2.3 g, 93%).

Description 647-Chloro-3-cyclopropylethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D64)

A mixture of D63 (2.3 g, 6.062 mmol) and phosphorous(V)oxychloride(0.848 g, 9.094 mmol) and DIPEA (0.792 ml, 4.547 mmol) in CH₃CN (24 ml)were heated at 150° C. under microwave irradiation for 15 min. Aftercooling, the resulting reaction mixture was poured into ice-water, andwashed with NaHCO₃ (aqueous sat. solution). The resulting mixture wasextracted with DCM. The organic phase was separated, dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by column chromatography(silica gel; DCM/EtOAc 100/0 to 90/10 as eluent). The desired fractionswere collected and concentrated in vacuo to yield intermediate D64 (0.9g, 51%).

Description 65 1′-(2,3-Dichloropyridin-4-yl)3,3-dimethyl-3H-spiro[benzo[c]furan-1,4′-piperidine (D65)

A mixture of intermediate D10 (0.35 g, 1.278 mmol),3,3-dimethyl-3H-spiro[benzo[c]furan-1,4′-piperidine [C.A.S 180160-92-3](0.333 g, 1.534 mmol) and DIPEA (0.534 ml, 3.068 mmol) in CH₃CN (5 ml)was heated in a sealed tube at 110° C. overnight. After cooling to r.t.the mixture was filtered through a pad of diatomaceous earth. Thefiltrate was concentrated in vacuo. The residue thus obtained waspurified by column chromatography (silica gel; DCM/MeOH up to 5% aseluent). The desired fractions were collected and concentrated in vacuo.The residue thus obtained was purified again by HPLC to yieldintermediate D65 (0.030 g, 5%).

Description 66[3-Chloro-4-(3,3-dimethyl-3H-spiro[benzo[c]furan-1,4′-piperidyl)-pyridin-2-yl]hydrazine(D66)

To a suspension of D65 (0.4 g, 1.101 mmol) in 1,4-dioxane (11 ml) wasadded hydrazine monohydrate (0.327 ml, 6.606 mmol). The reaction mixturewas heated at 160° C. under microwave irradiation for 30 min. Aftercooling, additional hydrazine monohydrate (20 eq.) was added. Then themixture was heated at 160° C. under microwave irradiation for 20 min,cooled and concentrated in vacuo. The residue was suspended in Na₂CO₃(aqueous sat. solution) and extracted with DCM. The organic phase wasseparated, dried (Na₂SO₄) and concentrated in vacuo to yieldintermediate D66 (0.38 g, 96%).

Description 673,3,3-trifluoropropanal-N′-{3′-chloro-4′-(3,3-dimethyl-3H-spiro[benzo[c]furan-1,4′-piperidyl]pyridin-2-yl)-hydrazone(D67)

A solution of D66 (0.38 g, 1.059 mmol) and3,3,3-trifluoropropionaldehyde (0.125 g, 1.112 mmol) in EtOH (10.6 ml)was heated at 78° C. for 2 h. The mixture was concentrated in vacuo toyield intermediate D67 (0.5 g).

Description 68 (4-Chloro-3-iodo-pyridin-2-yl)-hydrazine (D68)

To a suspension of D24 (4.7 g, 17.16 mmol) in 1,4-dioxane (240 ml), wasadded hydrazine monohydrate (5.096 ml, 102.96 mmol). The reactionmixture was heated at 80° C. overnight. After cooling, the resultingsolution was concentrated in vacuo. The residue thus obtained wasdissolved in DCM and washed with NaHCO₃ (aqueous sat. solution). Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The residue was treated with Et₂O. The solid obtained was filtered off.The filtrate was concentrated in vacuo to yield intermediate D68 (2.26g, 49%).

Description 69 Cyclopropyl-acetic acidN′-(4-chloro-3-iodo-pyridin-2-yl)-hydrazide (D69)

To a solution of D68 (3 g, 11.133 mmol) in dry DCM (40 ml) stirred at 0°C. was added Et₃N (3.081 ml, 22.266 mmol) and cyclopropyl-acetylchloride [C.A.S. 543222-65-5] (1.584 g, 13.359 mmol). The resultingreaction mixture was stirred at r.t. overnight. The mixture was washedwith NaHCO₃ (aqueous sat. solution). The organic phase was separated,dried (Na₂SO₄) and concentrated in vacuo to yield intermediate D69 (4.04g).

Description 708-Iodo-3-cyclopropylmethyl-7-chloro[1,2,4]triazolo[4,3-a]pyridine (D70)

Intermediate D69 (0.74 g, 2.389 mmol) was heated at 160° C. for 2 h.After cooling, the gum thus obtained was purified by short open columnchromatography (silica gel; DCM/EtOAc 100/0 to 50/50 as eluent). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate D70 (7 g, 55%) as a yellow solid. M.P. 246.7° C.

Description 718-Methyl-3-cyclopropylmethyl-7-chloro[1,2,4]triazolo[4,3-a]pyridine(D71)

To a mixture of D70 (0.6 g, 1.8 mmol) in toluene (15 ml) under anitrogen atmosphere were added methylboronic acid (0.538 g, 9 mmol),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine; S-Phos (0.171 g,0.36 mmol), palladium(II)acetate (0.04 g, 0.18 mmol) and K₂CO₃ (0.745 g,5.396 mmol). The reaction mixture was heated at 100° C. overnight. Aftercooling, the mixture was diluted with EtOAc and washed with water. Theorganic layer was separated and concentrated in vacuo. The residue waspurified by column chromatography (silica gel; DCM/EtOAc from 100/0 to20/80 as eluent). The desired fractions were collected and concentratedin vacuo to yield intermediate D71 (0.312 g, 78%) as a cream solid.

Description 721′-(benzyl)-spiro[isobenzofuran-1(3H),4′-piperidin]-3-thione (D72)

To a mixture of1′-(phenylmethyl)-spiro[isobenzofuran-1(3H),4′-piperidin]-3-one (25 g,85.2 mmol) [C.A.S. 37663-42-6] in toluene (600 ml), was added2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide(Lawesson's reagent) (34.47 g, 85.2 mmol was added. The reaction mixturewas heated at 140° C. for 2 h. After cooling, the mixture was pouredinto NH₄Cl (aqueous sat. solution) and extracted with DCM. The organicphase was separated, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by column chromatography (silica gel; DCM/MeOH 3%as eluent). The desired fractions were collected and concentrated invacuo to a residue that was purified by HPLC to yield intermediate D72(8 g, 30.3%).

Description 73N-benzyl-3,3-difluoro-3H-spiro[benzo[c]furan-1,4′-piperidine (D73)

To a stirred solution of D72 (8 g, 25.85 mmol) and tetrabutylammoniumdihydrogen trifluoride (48 g, 159 mmol) in DCM (1 L) was addedN-bromosuccinimide (11.2 g). The reaction mixture was stirred at r.t.for 6 hour. Then a mixture of NaHCO₃/NaHSO₃ (10% aqueous solution) wasadded and stirred for 30 min. The organic phase was separated, dried(MgSO₄) and concentrated in vacuo. The residue was purified by columnchromatography (silica gel; DCM/7M solution of NH₃ in MeOH up to 2% aseluent). The desired fractions were collected and concentrated in vacuoto give a residue that was purified on SFC to yield intermediate D73(1.3 g, 16%).

Description 74 3,3-diFluoro-3H-spiro[benzo[c]furan-1,4′-piperidine (D74)

To a stirred solution of D73 (1.3 g, 4.122 mmol) in DCM (450 ml), wasadded DIPEA (4 g). The resulting mixture was cooled to 0-5° C. and asolution of α-chloroethoxycarbonyl chloride (2.947 g, 20.611 mmol) inDCM (50 ml) was added dropwise. The mixture was stirred at r.t. for 2 hthen, concentrated in vacuo. The residue was dissolved in MeOH (400 ml),heated at reflux for 3 h and then concentrated in vacuo. The residue wasdissolved in EtOAc and washed with Na₂CO₃ (aqueous sat. solution). Theorganic phase was separated, dried (MgSO₄) and concentrated in vacuo.The residue was purified by column chromatography (silica gel; DCM/7Msolution of NH₃ in MeOH up to 5% as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate D74 (0.6 g,64.6%)

Description 752,6-Dioxo-4-(2-pyridinyl)-4-methyl-piperidine-3,5-dicarbonitrile (D75)

To a solution of 2-acetylpyridine (5 g, 41.275 mmol) and ethylcyanoacetate (9.805 g, 86.677 mmol) at 0° C., was added NH₃ (7M in MeOH,200 ml), was added. The reaction mixture was stirred at r.t. for 48 hand then concentrated in vacuo to give intermediate D75 (6 g, 57%)

Description 76 3-(2-Pyridinyl)-3-methyl-pentanedioic acid (D76)

To a mixture of D75 (6 g, 23.6 mmol) in water (3 ml) stirred at r.t.,sulfuric acid (3 ml) was carefully added. The resulting mixture washeated at 170° C. for 24 h. After cooling, NaOH (50% aqueous solution)was added dropwise (to afford pH 5-6). Then, MeOH was added to theaqueous mixture. The precipitate thus obtained was filtered and dried invacuo to yield intermediate D76 (3.5 g, 66.4%) as a green dark oil

Description 77 2,6-Dioxo-4-(2-pyridinyl)-4-methyl-piperidine (D77)

A solution of D76 (1.7 g, 7.616 mmol) and urea (1.143 g, 19.039 mmol) inMeOH (10 ml) was concentrated in vacuo. The homogeneous solid mixturethus obtained was heated at 180° C. for 3 h in a open flask. Aftercooling, the solid residue was suspended in water and extracted withEtOAc. The organic phase was separated, dried (Na₂SO₄) and concentratedin vacuo. The residue was purified by column chromatography (silica gel;EtOAc as eluent). The desired fractions were collected and concentratedin vacuo to yield intermediate D77 (0.6 g, 38.58%)

Description 78 4-(2-Pyridinyl)-4-methyl-piperidine (D78)

To a mixture of intermediate D77 (0.6 g, 2.938 mmol) in dry THF (25 mL),was added BH₃-THF (10.283 mL, 1M) at r.t. and the reaction was heated atreflux for 24 h. The reaction mixture was cooled to r.t. and quenched bythe careful addition of 6 N HCl (50 mL). After the gas evolution ceased,the mixture was concentrated under reduced pressure and the residue thusobtained was treated with additional 6 N HCl (150 mL). The mixture washeated at reflux for 2 h, then cooled at r.t. and treated with a 2Msolution of NaOH to pH 11. The resulting mixture was heated at refluxfor 2 h. After cooling, the mixture was extracted with EtOAc to yieldintermediate D78 (0.4 g, 77%) as an orange oil

Description 79N′-[4-(benzyloxy)-3-(trifluoromethyl)pyridin-2-yl]-2-(2-pyridinyl)aceticacid hydrazide (D79)

To a stirred solution of D27 (1.851 g, 6.536 mmol), 2-pyridine aceticacid, hydrochloride (1:1) (0.674 mg, 3.883 mmol), DIPEA (2.434 ml,14.122 mmol) in DMF (20 ml) at r.t. was added2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate [C.A.S.148893-10-1] (1.477 g, 3.883 mmol). Theresulting reaction mixture was stirred at r.t. overnight. Water wasadded to the mixture and the precipitate obtained was filtered off,washed with water and dried in vacuo to yield intermediate D79 (1.26 g,88.7%).

Description 807-Chloro-3-(2-pyridinyl)methyl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D80)

D79 (1.1 g, 2.734 mmol), phosphorous(V)oxychloride (0.382 g, 4.101 mmol)and DIPEA (0.357 ml, 2.05 mmol) in CH₃CN (2 ml) were heated at 150° C.under microwave irradiation for 15 min. After cooling, the resultingreaction mixture was poured in ice/water, washed with NaHCO₃ (aqueoussat. solution) and extracted with DCM. The organic phase was separated,dried (Na₂SO₄) and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel; DCM/EtOAc from 100/0 to 20/80 aseluent). The desired fractions were collected and concentrated in vacuoto yield intermediate D80 (0.35 g, 41%).

Description 818-Ethyl-3-cyclopropylmethyl-7-chloro[1,2,4]triazolo[4,3-a]pyridine (D81)

To a mixture of intermediate D70 (0.6 g, 1.8 mmol) in toluene (14 ml)under a nitrogen atmosphere were added ethylboronic acid (0.665 g, 9mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine; X-Phos(0.171 g, 0.36 mmol), palladium(II) acetate (0.04 g, 0.18 mmol) andK₂CO₃ (0.745 g, 5.396 mmol). The reaction mixture was heated at 100° C.overnight. After cooling, the mixture was diluted with EtOAc and washedwith water. The organic layer was separated and concentrated in vacuo.The residue was purified by column chromatography (silica gel; DCM/EtOAcfrom 100/0 to 20/80 as eluent). The desired fractions were collected andconcentrated in vacuo to give a residue that was purified by HPLC toyield intermediate D81 (0.053 g, 12.6%).

Description 828-Cyclopropyl-3-cyclopropylmethyl-7-chloro[1,2,4]triazolo[4,3-a]pyridine(D82)

To a mixture of D70 (0.6 g, 1.8 mmol) in toluene (14 ml) under anitrogen atmosphere were added potassium cyclopropyltrifluoroborate(0.799 g, 5.4 mmol), bis(adamantan-1-yl)(butyl)phosphine (0.019 g, 0.054mmol), palladium(II)acetate (8.15 mg, 0.036 mmol) and Cs₂CO₃ (1.758 g,5.4 mmol). The reaction mixture was heated at 100° C. overnight. Aftercooling, additional potassium cyclopropyltrifluoroborate (0.7 g, 4.71mmol), bis(adamantan-1-yl)(butyl)phosphine (0.019 g, 0.054 mmol) andpalladium(II) acetate (8.15 mg, 0.036 mmol) were added to the reactionmixture, which was then heated at 100° C. for 48 h. After cooling, morepotassium cyclopropyltrifluoroborate (0.35 g, 2.37 mmol) was added andheated at 100° C. for 3 days. After cooling, the reaction mixture wasdiluted with EtOAc and washed with water. The organic layer wasseparated and concentrated in vacuo. The residue was purified by columnchromatography (silica gel; DCM/EtOAc from 100/0 to 60/40 as eluent).The desired fractions were collected and concentrated in vacuo to yieldintermediate D82 (0.217 g, 48.7%) as a yellow solid.

Description 831-Benzyl-4-[4-fluoro-2-(1-hydroxy-1-methyl-ethyl)-phenyl]-4-hydroxypiperidine(D83)

To an anhydrous THF (50 mL) cooled at −70° C. stirred under nitrogen a2.5 M solution of n-BuLi (4.22 mL, 10.54 mmol) was added. Then2-bromo-5-fluoro-α,α-dimethyl-benzylalcohol (1.17 g, 5.02 mmol)[C.A.S.853271-16-6] was added dropwise. The resulting mixture wasstirred at −70° C. for 2 h. Then a solution of 1-benzylpiperidin-4-one(1.33 g, 7.028 mmol) in anhydrous THF (10 ml) was added dropwise. Then,the resulting solution was stirred at r.t. overnight. The reactionmixture was poured into NH₄Cl (aqueous sat. solution) at 5-10° C. Theresulting aqueous solution was extracted with DCM. The organic layer wasseparated and concentrated in vacuo. The residue was purified by columnchromatography (silica gel; heptane/EtOAc from 100/0 to 60/40 aseluent). The desired fractions were collected and concentrated in vacuoto yield intermediate D83 (0.4 g, 23%).

Description 84N-Benzyl-3,3-dimethyl-5-fluoro-3H-spiro[benzo[c]furan-1,4′-piperidine](D84)

To a stirred solution of D83 (0.4 g, 1.165 mmol) in toluene (8 ml) atr.t., borontrifluoride diethyletherate (1.463 ml, 11.647 mmol) was addeddropwise. The resulting mixture was stirred at r.t. overnight. Thenadditional borontrifluoride diethyletherate (0.4 ml) was added andstirred overnight. Then, the reaction mixture was poured into NaOH (2Naqueous solution) and stirred for 10 min. The aqueous solution wasextracted with DCM. The organic layer was separated, washed with Na₂CO₃(aqueous sat. solution), dried (Na₂SO₄) and concentrated in vacuo toyield intermediate D84 (0.271 g, 72%).

Description 853,3-Dimethyl-5-fluoro-3H-spiro[benzo[c]furan-1,4′-piperidine] (D85)

A solution of intermediate D84 (0.271 g, 0.833 mmol) in EtOH (17 ml) washydrogenated in a H-Cube reactor® (1 ml/min, Pd/C 10% cartridge, full H₂mode, 80° C.). The solvent was concentrated in vacuo to yieldintermediate D85 (0.168 g, 86%) as off-white solid.

Description 863-Cyclopropylmethyl-7-[4-phenyl-piperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine(D86)

A stirred suspension of final compound E26 (0.225 g, 0.613 mmol),triethylsilane (0.195 ml, 1.227 mmol), Pd(PPh₃)₄ (0.071, 0.0613 mmol)and DIPEA (0.331 ml, 1.533 mmol) in propionitrile (3 ml) was heated at200° C. under microwave irradiation for 30 min. After cooling, thereaction mixture was refilled with additional triethylsilane (0.195 ml)and Pd(PPh₃)₄ (0.050) and heated at 200° C. under microwave irradiationfor 30 min. After cooling, the mixture was washed with NaHCO₃ (aqueoussat. solution) and extracted with DCM. The organic layer was separated,dried (Na₂SO₄) and concentrated in vacuo. The residue was purified againby column chromatography (silica gel; DCM/EtOAc from 100/0 to 10/90 aseluent). The desired fractions were collected and concentrated in vacuoto yield intermediate D86 (0.089 g, 43.7%).

Description 877-Vinyl-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D87)

A suspension of D29 (1.65 g, 5.986 mmol), vinylboronic acid pinacolester (1.218 ml, 7.183 mmol), Pd(PPh₃)₄ (0.346, 0.3 mmol) and NaHCO₃(aqueous sat. solution, 12.5 ml) in 1,4-dioxane (64.5 ml) was heated at150° C. under microwave irradiation for 13 min. After cooling, theresulting reaction mixture was diluted with EtOAc/water and filteredthrough a pad of diatomaceous earth. The filtrate was washed with waterand NaCl (aqueous sat. solution) and extracted with EtOAc. The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified again by column chromatography (silica gel;DCM/EtOAc from 100/0 to 60/40 as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate D87 (1.34 g,83.7%).

Description 887-carboxaldehyde-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D88)

A solution of D87 (6.24 g, 21.014 mmol), sodium periodate (13.484 g,63.041 mmol), osmium tetroxide (2.5% in tert-butanol, 10.873 ml, 0.841mmol) in water (55 ml) and 1,4-dioxane (221 ml) was stirred at r.t. for2 h. The resulting reaction mixture was diluted with EtOAc/water andfiltered through a pad of diatomaceous earth. The filtrate was extractedwith EtOAc. The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. The solid residue was washed with Et₂O, filteredand dried in vacuo to yield intermediate D88 (3.84 g, 67.9%).

Description 897-Hydroxymethyl-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D89)

To a solution of D88 (1.73 g, 6.426 mmol) in MeOH (58 ml) stirred at 0°C., was added portionwise sodium borohydride (0.243, 6.426 mmol). Theresulting mixture was stirred at r.t. for 1 h. The resulting mixture wasconcentrated in vacuo. The residue was treated with water and NaCl(aqueous sat. solution) and extracted with EtOAc. The organic layer wasseparated and concentrated in vacuo. The residue was purified by columnchromatography (silica gel; DCM/7M solution of NH₃ in MeOH up to 5% aseluent). The desired fractions were collected and concentrated in vacuoto yield intermediate D89 (1.015 g, 58%) as a brown syrup.

Description 907-(methylsulfonyloxy)methyl-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D90)

To a solution of D89 (1.341 g, 9.678 mmol) and Et₃N (0.778 ml, 5.612mmol) in DCM (42 ml) stirred at 0° C., was added dropwise methylsulfonylchloride (0.749 ml, 9.678 mmol) and stirred at r.t. for 2 h. Theresulting mixture was treated with NaHCO₃ (aqueous sat. solution) andextracted with DCM. The organic layer was separated and concentrated invacuo to yield intermediate D90 (2.6 g, 87%).

Description 917-(1-hydroxyethyl)-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D91)

To a solution of D88 (0.3 g, 1.114 mmol) in THF (20 ml) cooled at −20°C. stirred under nitrogen was added dropwise a 1.4 M solution ofmethylmagnesium bromide (0.876 mL, 1.226 mmol). The resulting mixturewas stirred at −20° C. for 30 min. The reaction mixture was treated withNH₄Cl (aqueous sat. solution) and extracted with EtOAc. The organiclayer was separated and concentrated in vacuo. The residue was purifiedby column chromatography (silica gel; DCM/7M solution of NH₃ in MeOH upto 5% as eluent). The desired fractions were collected and concentratedin vacuo to yield intermediate D91 (0.287 g, 90%).

Description 927-[1-(4-methylphenylsulfonyloxy)ethyl]-3-cyclopropylmethyl-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine(D92)

To an ice-cooled stirred solution of D91 (0.154 g, 0.54 mmol) in DCM(1.5 ml) was added pyridine (0.130 ml) and 4-benzenesulfonyl chloride(0.205 g, 1.08 mmol) dropwise. The resulting mixture was stirred at r.t.for 5 days. The reaction was treated with 2N HCl (aqueous solution) andextracted with DCM. The organic layer was separated and concentrated invacuo. The residue was purified by column chromatography (silica gel;DCM/EtOAc from 100/0 to 50/50 as eluent). The desired fractions werecollected and concentrated in vacuo to yield intermediate D92 (0.142 g,50%).

Description 937-Vinyl-3-cyclopropylmethyl-8-chloro[1,2,4]triazolo[4,3-a]pyridine (D93)

To a solution of D13 (12 g, 35.976 mmol), vinylboronic acid pinacolester (6.713 ml, 39.573 mmol) in NaHCO₃ (aqueous sat. solution, 90 ml)in 1,4-dioxane (360 ml) under a nitrogen atmosphere was added Pd(PPh₃)₄(2.079, 1.8 mmol). The resulting mixture was heated in a sealed tube at100° C. for 16 h. After cooling, the resulting reaction mixture wasdiluted with NaHCO₃ (aqueous sat. solution) and extracted with DCM. Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by column chromatography (silica gel; DCM/EtOAcfrom 100/0 to 20/80 as eluent). The desired fractions were collected andconcentrated in vacuo. The residue thus obtained was triturated withDIPE to yield intermediate D93 (6.09 g, 72%) as a yellow solid.

Description 948-chloro-3-(cyclopropylmethyl)[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde(D94)

To a solution of D93 (6.09 g, 25.059 mmol) in 1,4-dioxane (320 ml)stirred at r.t. was added osmium tetroxide (2.5% in tert-butanol, 13.483ml, 1.042 mmol). Then a solution of sodium periodate (16.721 g, 78.177mmol) in water (80 ml) was added dropwise. The resulting mixture wasstirred at r.t. for 2 h, then, diluted with water and extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄) and concentratedin vacuo. The solid residue was triturated with Et₂O, filtered and driedin vacuo to yield intermediate D94 (5.48 g, 89%) as a cream solid.

Description 957-Hydroxymethyl-3-cyclopropylmethyl-8-chloro[1,2,4]triazolo[4,3-a]pyridine(D95)

To a stirred solution of D94 (3 g, 12.73 mmol) in MeOH (100 ml) at 0°C., was added portionwise sodium borohydride (0.482, 12.73 mmol). Theresulting mixture was stirred at r.t. for 2 h. The resulting mixture wasconcentrated in vacuo. The residue was treated with NaCl (aqueous sat.solution) and extracted with DCM. The organic layer was separated andconcentrated in vacuo. The residue was purified by column chromatography(silica gel; DCM/7M solution of NH₃ in MeOH up to 6% as eluent). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate D95 (2.03 g, 67%) as a white solid.

Description 967-Chloromethyl-3-cyclopropylmethyl-8-chloro[1,2,4]triazolo[4,3-a]pyridine(D96)

To a solution of D95 (2 g, 8.414 mmol) and Et₃N (3.5 ml, 25.243 mmol) inDCM (80 ml) stirred at 0° C., was added dropwise methylsulfonyl chloride(1.954 ml, 25.243 mmol) and the mixture was stirred at r.t. for 16 h,then diluted with NaHCO₃ (aqueous sat. solution) and extracted with DCM.The organic layer was separated and concentrated in vacuo to yieldintermediate D96 (2.4 g, 100%) as a cream solid.

Description 973-Bromo-8-cyano-7-(4-phenylpiperidinyl)[1,2,4]triazolo[4,3-a]pyridine(D97)

To a stirred solution of intermediate D8 (0.49 g, 1.615 mmol) in DCM (20ml) was added N-bromosuccinimide (0.316 g, 1.777 mmol). The resultingmixture was stirred at r.t. for 1.5 h. The mixture was carefully washedwith NaHCO₃ (aqueous sat. solution) and extracted with DCM. The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuo to yieldintermediate D97 (0.48 g, 78%).

Description 988-Methyl-3-cyclopropylmethyl-7-chloro[1,2,4]triazolo[4,3-a]pyridine(D98)

To a mixture of intermediate D70 (1 g, 3 mmol) in toluene (25 ml) undera nitrogen atmosphere were added methylboronic acid (0.897 g, 15 mmol),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine; X-Phos (0.286 g,0.6 mmol), palladium(II)acetate (0.067 g, 0.3 mmol) and K₂CO₃ (1.243 g,9 mmol). The reaction mixture was heated at 100° C. for two days. Aftercooling, the mixture was diluted with EtOAc and washed with water. Theorganic layer was separated and concentrated in vacuo. The residue waspurified by column chromatography (silica gel; DCM/EtOAc from 100/0 to0/100 as eluent). The desired fractions were collected and concentratedin vacuo to yield intermediate D98 (0.365 g, 55%).

Description 994-(3-Cyclopropylmethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (D99)

A mixture of D98 (0.358 mg, 1.614 mmol),N-(tert-butoxycarbonyl)-3,6-dihydro-2H-pyridine-4-boronic acid pinacolester (0.6 g, 1.937 mmol) and Pd(PPh₃)₄ (0.0933 g, 0.0801 mmol) inNaHCO₃, (3.5 ml, aqueous sat. solution) and 1,4-dioxane (9 ml) washeated at 150° C. under microwave irradiation for 5 min. After cooling,the mixture was refilled with additionalN-(tert-butoxycarbonyl)-3,6-dihydro-2H-pyridine-4-boronic acid pinacolester (0.5 g) and Pd(PPh₃)₄ (0.072 g) and NaHCO₃, (1 ml, aqueous sat.solution). The mixture was heated at 150° C. under microwave irradiationfor 20 min. After cooling to r.t. the mixture was diluted withEtOAc/H₂O, filtered through a pad of diatomaceous earth and washed withEtOAc. The organic phase was collected, dried (Na₂SO₄) and concentratedin vacuo. The crude product was purified by column chromatography(silica gel; EtOAc/7M solution of NH₃ in MeOH up to 6% as eluent). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate D99 (0.458 g, 77%).

Description 100

4-(3-Cyclopropylmethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-piperidine-1-carboxylicacid tert-butyl ester (D100)

A solution of intermediate D99 (0.606 g, 1.645 mmol) in EtOH (35 ml) washydrogenated in a H-Cube® reactor (1 ml/min, Pd/C 10% cartridge, full H₂mode, 80° C.). The solvent was concentrated in vacuo and the residue waspurified by column chromatography (silica gel; EtOAc/7M solution of NH₃in MeOH up to 6% as eluent). The desired fractions were collected andconcentrated in vacuo to yield intermediate D100 (0.214 g, 35%).

Description 101

3-Cyclopropylmethyl-8-methyl-7-piperidin-4-yl-[1,2,4]triazolo[4,3-a]pyridine(D101)

To a stirred solution of D100 (0.207 g, 0.560 mmol) in dry DCM (3.5 ml),was added trifluoroacetic acid (1.01 ml). The mixture was stirred atr.t. for 2 h and then concentrated in vacuo. The residue was basifiedwith NaOH 50% (aqueous solution) and extracted with DCM. The organicphase was separated, dried (Na₂SO₄) and concentrated in vacuo to yieldintermediate D101 (0.149 g, 99%).

Example 18-Chloro-3-cyclopropylmethyl-7-[(4-phenyl-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine(E1)

D39 (0.268 g, 0.672 mmol) and phosphorous(V)oxychloride (0.125 ml, 1.344mmol) in CH₃CN (3 ml) was heated at 150° C. under microwave irradiationfor 5 min. After cooling, NaHCO₃ (aqueous sat. solution) was added andthe resulting mixture was extracted with EtOAc (three times). Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by column chromatography (silica gel;DCM/MeOH up to 3% as eluent). The desired fractions were collected andconcentrated in vacuo to yield final compound E1 (0.112 g, 43.8%) as awhite solid.

Example 23-Cyclopropylmethyl-7-(4-fluoro-4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine(E2)

A suspension of D32 (0.37 g, 0.848 mmol), DIPEA-polymer supported (0.652g, 2.543 mmol, 3.9 mmol/g), triphenylphosphine-polymer supported (1.77g, 2.119 mmol, 1.8 mmol/g) and trichloroacetonitrile (0.102 ml, 1.017mmol) in DCE (10 ml) was heated at 150° C. under microwave irradiationfor 10 min. After cooling, the mixture was filtered through a pad ofdiatomaceous earth and washed with DCM and MeOH. The filtrate wasconcentrated in vacuo and the residue thus obtained was purified bycolumn chromatography (silica gel; DCM/EtOAc up to 40% as eluent). Thedesired fractions were collected and concentrated in vacuo. The residuewas subjected to preparative Supercritical fluid purification (pyridine20 mm; mobile phase, isocratic 85% CO₂, 15% MeOH) yielding compound E2(0.1 g, 28%).

Example 38-Chloro-7-(4-fluoro-4-phenyl-1-piperidinyl)-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine(E3)

A suspension of D₂₀ (7.768 g, 18.03 mmol), DIPEA-polymer supported(13.869 g, 54.09 mmol, 3.9 mmol/g), triphenylphosphine-polymer supported(25.042 g, 45.075 mmol, 1.8 mmol/g) and trichloroacetonitrile (2.169 ml,21.636 mmol) in DCE (180 ml) was heated at 150° C. under microwaveirradiation for 10 min. After cooling, the mixture was filtered througha pad of diatomaceous earth and washed with DCM and MeOH. The filtratewas concentrated in vacuo and the residue was purified by columnchromatography (silica gel; DCM/EtOAc up to 40% as eluent). The desiredfractions were collected and concentrated in vacuo. The residue wassubjected to preparative Supercritical fluid purification (pyridine 20mm; mobile phase, isocratic 83% CO₂, 17% MeOH) yielding final compoundE3 (2.357 g, 31%).

Example 43-Butyl-7-(4-phenyl-1-piperidinyl)-8-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridine(E4)

D35 (0.44 g, 1.046 mmol) and phosphorus(V)oxychloride (0.146 ml, 1.57mmol) in DCE (5 ml) was heated at 150° C. under microwave irradiationfor 5 min. After cooling, the mixture was diluted with DCM and washedwith NaHCO₃ (aqueous sat. solution). The organic layer was separated,dried (Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby column chromatography (silica gel; DCM/7M solution of NH₃ in MeOH upto 3% as eluent). The desired fractions were collected and concentratedin vacuo to yield final compound E4 (0.160 g, 38%).

Example 58-Chloro-3-(ethoxymethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine(E5)

D17 (0.544 g, 1.4 mmol) and phosphorous(V)oxychloride (0.13 ml, 1.4mmol) in DCE (5 ml) was heated at 150° C. under microwave irradiationfor 5 min. After cooling, the mixture was diluted with DCM and washedwith NaHCO₃ (aqueous sat. solution). The organic layer was separated,dried (Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby column chromatography (silica gel; DCM/7M solution of NH₃ in MeOH upto 3% as eluent). The desired fractions were collected and concentratedin vacuo to yield compound E5 (0.175 g, 34%).

Example 61′-[8-Chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′piperidine] (E6)

To a stirred solution of compound D13 (0.2 g, 0.6 mmol) in toluene (3ml) were added spiro[isobenzofuran-1(3H),4′-piperidine]hydrochloride[CAS 37663-44-8] (0.147 g, 0.779 mmol), palladium(II)acetate (0.007 g,0.03 mmol), Cs₂CO₃ (0.488 g, 1.5 mmol) and BINAP (0.028 g, 0.045 mmol).The reaction mixture was heated at 95° C. for 16 h in a sealed tube.After cooling to r.t. the mixture was diluted with EtOAc and filteredthrough a pad of diatomaceous earth. The filtrate was washed with NaHCO₃(aqueous sat. solution) and NaCl (aqueous sat. solution). The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuo. Theresidue thus obtained was purified by column chromatography (silica gel;DCM/7M solution of NH₃ in MeOH up to 1% as eluent). The desiredfractions were collected and concentrated in vacuo. The residue thusobtained was purified again by column chromatography (silica gel;DCM/EtOAc up to 60% as eluent). The desired fractions were collected andconcentrated in vacuo. The residue thus obtained was triturated withdiisopropyl ether to yield final compound E6 (0.074 g, 31%) as a paleyellow solid.

Example 72-[1-[8-Chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-α,α-dimethyl-benzenemethanol(E7)

To a stirred solution of compound D13 (003 g, 0.0899 mmol) in toluene (1ml) were added D41 (0.0256 g, 0.117 mmol), palladium(II)acetate (1.02mg, 0.0045 mmol), Cs₂CO₃ (0.0733 g, 0.225 mmol) and BINAP (4.2 mg,0.0067 mmol). The reaction mixture was heated at 95° C. for 16 h in asealed tube. An additional amount of palladium(II)acetate (1.02 mg,0.0045 mmol) and BINAP (4.2 mg, 0.0067 mmol) was added to the reactionmixture, which was then heated at 95° C. for 6 h under microwaveirradiation. After cooling to r.t. the mixture was diluted with EtOAcand filtered through a pad of diatomaceous earth. The filtrate waswashed with NaCl (aqueous sat. solution). The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The residue thusobtained was purified by column chromatography (silica gel; DCM/7Msolution of NH₃ in MeOH up to 3% as eluent). The desired fractions werecollected and concentrated in vacuo to yield E7 (0.02 g, 52%).

Example 81′-[8-Chloro-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-spiro[isobenzofuran-1(3H),4′-piperidine](E8)

A solution of D23 (0.369 g, 0.836 mmol) and phosphorus(V)oxychloride(0.156 ml, 1.673 mmol) in CH₃CN (5 ml) was heated at 150° C. undermicrowave irradiation for 5 min. Additional phosphorous(V)oxychloride(0.5 eq) was added to the reaction mixture, which was then irradiated at150° C. for 5 min. After cooling, NaHCO₃ (aqueous sat. solution) wasadded and the resulting mixture was extrated with EtOAc. The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM/MeOH upto 3% as eluent). The desired fractions were collected and concentratedin vacuo. The residue thus obtained was triturated with DIPE to yieldfinal compound E8 (0.015 g, 4%).

Example 98-Chloro-3-(2-methylpropyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine(E9)

D16 (0.440 g, 1.137 mmol) and phosphorus(V)oxychloride (0.229 mg, 1.365mmol) in DCE (4 ml) was heated at 150° C. under microwave irradiationfor 5 min. After cooling, the resulting mixture was concentrated invacuo. The residue was dissolved in DCM, washed with NaHCO₃ (aqueoussat. solution) and concentrated in vacuo. The crude product was purifiedby column chromatography (silica gel; DCM/MeOH up to 3% as eluent). Thedesired fractions were collected and concentrated in vacuo. The residuethus obtained was triturated with DIPE to yield final compound E9 (0.320g, 76%).

Example 103-ethyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile(E10)

A solution of D7 (0.05 g, 0.17 mmol) and triethylorthopropionate (0.462ml, 2.556 mmol) in xylene (1 ml) was heated in a sealed tube at 180° C.for 2 h. After cooling, the resulting mixture was concentrated in vacuo.The residue thus obtained was triturated with Et₂O to yield finalcompound E10 (0.042 g, 74%).

Example 113-(4-Morpholinylmethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile(E11)

To a solution of D9 (0.065 g, 0.196 mmol) in DCM (2.5 ml) were addedmorpholine (0.026 g, 0.294 mmol) and sodium triacetoxy-borohydride(0.062 mg, 0.294 mmol). The resulting mixture was stirred at r.t. for 1day. The reaction mixture was washed with H₂O, dried (MgSO₄) andconcentrated in vacuo. The crude product thus obtained was purified bycolumn chromatography (silica gel; DCM/MeOH up to 3% as eluent). Thedesired fractions were collected and concentrated in vacuo to yieldfinal compound E11 (0.04 g, 51%) as a white solid.

Example 127-(4-phenyl-1-piperidinyl)-3-[(4-phenyl-1-piperidinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile(E12)

To a solution of D8 (0.301 g, 0.992 mmol) in acetic acid (4.5 ml) wereadded 4-phenylpiperidine (0.160 g, 0.992 mmol) and formaldehyde (0.223ml, 0.992 mmol; 37%). The resulting mixture was heated in a sealed tubeat 80° C. for 16 h. The reaction mixture was diluted with DCM and washedwith 2M NaOH. The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo. The crude product thus obtained was purified bycolumn chromatography (silica gel; DCM/7M solution of NH₃ in MeOH up to2% as eluent). The desired fractions were collected and concentrated invacuo to yield a residue that was purified by HPLC (C18Xbridge 19×100;mobile phase AcONH4/CH₃CN gradient as eluent). The desired fractionswere collected and concentrated in vacuo to yield final compound E12(0.085 g, 18%).

Example 133-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile(E13)

A mixture of compound D5 (0.2 g, 0.86 mmol), 4-phenylpiperidine (0.166g, 1.031 mmol), K₂CO₃ (0.148 g, 1.074 mmol) in CH₃CN (5 ml) was heatedin a sealed tube at 150° C. under microwave irradiation for 5 min. Themixture was then cooled to r.t. and the solvents evaporated in vacuo.The residue thus obtained was purified by column chromatography (silicagel; DCM/7M solution of NH₃ in MeOH up to 3% as eluent). The desiredfractions were collected and concentrated in vacuo to yield compound E13as yellow solid (0.150 g, 49%).

Example 143-Cyclobutyl-7-(4-phenyl-1-piperidinyl)-1,2,4-triazolo[4,3-a]pyridine-8-carbonitrile(E14)

A solution of D7 (0.190 g, 0.648 mmol), DIPEA (0.226 g, 1.295 mmol),triphenylphosphine (0.510 g, 1.943 mmol), trichloroacetonitrile (0.13ml, 1.295 mmol) and cyclobutanecarboxylic acid [C.A.S. 3721-95-7] (0.065g, 0.648 mmol) in DCE (10 ml) was heated at 150° C. under microwaveirradiation for 18 min. After cooling, the mixture was filtered througha pad of diatomaceous earth. The filtrate was washed with water, dried(MgSO₄) and concentrated in vacuo. The residue was purified by columnchromatography (silica gel; DCM/MeOH up to 5% as eluent). The desiredfractions were collected and concentrated in vacuo. The residue wastriturated with Et₂O yielding compound E14 (0.06 g, 26%).

Example 158-Chloro-3-(cyclopropylmethyl)-7-(4-trifluoromethyl-4-phenyl-piperidin-1-yl)-1,2,4-triazolo[4,3-a]pyridine(E15)

To a stirred solution of intermediate D13 (1 g, 2.998 mmol) in toluene(10 ml) were added intermediate D47 (0.962 g, 4.197 mmol),palladium(II)acetate (34 mg, 0.15 mmol), Cs₂CO₃ (1.465 g, 4.497 mmol)and B1NAP (0.14 g, 0.225 mmol) and the reaction mixture was heated at95° C. for 16 h in a sealed tube. After cooling to r.t. the mixture wasconcentrated in vacuo and the resulting residue was suspended in waterand extracted with DCM. The organic layer was separated, dried (Na₂SO₄),concentrated in vacuo and purified by column chromatography (silica gel;DCM/7M solution of NH₃ in MeOH up to 3% as eluent). The desiredfractions were collected and concentrated in vacuo. The residue thusobtained was triturated with EtOAc, diisopropyl ether and EtOH to yieldcompound E15 (0.503 g, 39%).

Example 161′-[8-Chloro-3-(2,2,2-trifluoroethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]-spiro[1-benzofuran-3,4′-piperidine](E16)

A solution of intermediate D50 (1.393 g, 3.16 mmol),phosphorus(V)oxychloride (0.333 ml, 3.476 mmol) and DIPEA (0.605 ml,3.476 mol) in DCE (15 ml) was heated at 150° C. under microwaveirradiation for 5 min. Additional phosphorous(V) oxychloride (0.6 eq)and diisopropyletheylamine (0.6 eq) were added to the reaction mixture,which was then irradiated at 150° C. for 5 min. After cooling, thereaction mixture was washed with NaHCO₃ (aqueous sat. solution). Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by column chromatography (silica gel;DCM/MeOH up to 5% as eluent). The desired fractions were collected andconcentrated in vacuo. The residue thus obtained was triturated withDIPE to yield final compound E16 (0.307 g, 23%).

Example 171′-[3-cyclopropylmethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]-spiro[1-benzofuran-3,4′-piperidine](E17)

A mixture of intermediate D29 (0.13 g, 0.472 mmol),4-spiro-[3-(2,3-dihydro-benzofuran)]piperidine [CAS 171-77-7] (0.178 g,0.943 mmol) and DIPEA (0.493 ml, 2.83 mmol) in CH₃CN (3 ml) was heatedat 180° C. under microwave irradiation for 1 h. After cooling, NaHCO₃(aqueous sat. solution) was added and the resulting mixture wasextracted with EtOAc. The organic layer was separated, dried (Na₂SO₄)and concentrated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/EtOAc up to 25% as eluent). The desiredfractions were collected and concentrated in vacuo. The residue thusobtained was triturated with DIPE to yield final compound E17 (0.115 g,57%).

Example 187-(4-Fluoro-4-phenylpiperidin-1-yl)-3-[(1-methylethoxy)methyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine(E18)

A suspension of intermediate D51 (0.245 g, 0.539 mmol), DIPEA-polymersupported (0.616 g, 2.156 mmol, 3.5 mmol/g), triphenylphosphine-polymersupported (0.61 g, 1.348 mmol, 2.21 mmol/g) and trichloroacetonitrile(0.065 ml, 0.647 mmol) in DCE (12 ml) was heated at 150° C. undermicrowave irradiation for 15 min. After cooling, the mixture wasfiltered through a pad of diatomaceous earth and washed with DCM andMeOH. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography (silica gel; DCM/EtOAc up to 80% aseluent). The desired fractions were collected and concentrated in vacuo.The residue was crystallized from Et₂O/DIPE yielding final compound E18(0.69 g, 29%).

Example 433-(Cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine(E43)

A mixture of intermediate D29 (22.1 g, 7.618 mmol), phenylpiperidine(1.734 g, 9.142 mmol) and DIPEA (2.654 ml, 15.236 mmol) in CH₃CN (8.5ml) was heated at 180° C. under microwave irradiation for 20 min. Aftercooling, the mixture was concentrated in vacuo. The crude product waspurified by column chromatography (silica gel; DCM/7M solution of NH₃ inMeOH up to 6% as eluent followed by DCM/EtOAc from 50/50 to 0/100). Thedesired fractions were collected and concentrated in vacuo. The crudeproduct was triturated with DIPE to yield final compound E43 (0.93 g,30.4%).

Example 2973-(Cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridinehydrochloride salt (E297)

To a stirred solution of final compound E43 (0.498 g, 1.244 mmol) in1,4-dioxane (30 ml) and MeOH (2 ml) was added dropwise HCl (4M in1,4-dioxane, few drops). The resulting suspension was concentrated invacuo. The solid residue was triturated with acetone, filtered and driedin vacuo to yield final compound E297 (0.482 g, 88.7%) as a white solid.

Example 1008-Chloro-3-(2,2,2-trifluoroethyl)-7-(3,3-dimethyl-4-phenyl-piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(E100)

A solution of intermediate D57 (0.463 g, 1.048 mmol) andphosphorus(V)oxychloride (0.146 ml, 1.572 mmol) in CH₃CN (11 ml) washeated at 150° C. under microwave irradiation for 10 min. After cooling,additional phosphorous(V)oxychloride (0.21 eq) was added to the reactionmixture, which was then irradiated at 150° C. for 10 min. After cooling,the reaction mixture was poured over a stirred NaHCO₃ aqueous sat.solution at 0° C. The aqueous solution was extracted with EtOAc. Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The crude product was purified by column chromatography (silica gel;DCM/7M solution of NH₃ in MeOH up to 6% as eluent). The desiredfractions were collected and concentrated in vacuo. The residue thusobtained was triturated with DIPE to yield final compound E100 (0.242 g,54%).

Example 1121′-[3-cyclopropylmethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]-3,3-dimethyl-3H-spiro[benzo[c]furan-1,4′-piperidine](E112)

A mixture of intermediate D29 (0.25 g, 0.907 mmol),3,3-dimethyl-3H-spiro[benzo[c]furan-1,4′-piperidine [C.A.S 180160-92-3](0.25 g, 1.15 mmol) and DIPEA (0.826 ml, 4.602 mmol) in CH₃CN (5 ml) washeated at 180° C. under microwave irradiation for 20 min. After cooling,the solvent was concentrated in vacuo. The crude product was purified bycolumn chromatography (silica gel; DCM/EtOAc 100/0 to 50/50, then DCM/7Msolution of NH₃ in MeOH up to 5% as eluent). The desired fractions werecollected and concentrated in vacuo to yield final compound E112 (0.2 g,38%).

Example 1191′-[3-cyclopropylmethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]-spiro[furo[2,3-b]pyridine-3(2H),4′-piperidine](E119)

A mixture of intermediate D29 (0.13 g, 0.472 mmol), D60 (0.045 g, 0.239mmol) and DIPEA (0.075 ml, 0.435 mmol) in CH₃CN (1 ml) was heated at180° C. under microwave irradiation for 20 min. After cooling,additional DIPEA (0.075 ml, 0.435 mmol) was added to the reactionmixture, which was then irradiated at 180° C. for 10 min. After cooling,the mixture was filtered through a pad of diatomaceous earth andextracted with DCM. The solvent was concentrated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM/MeOH(NH₃)up to 3%, then, DCM/EtOAc 100/0 to 50/50 as eluent). The desiredfractions were collected and concentrated in vacuo to yield finalcompound E119 (0.036 g, 38%) as a cream solid.

Example 1211′-[3-cyclopropylmethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]-4-phenyl-4,7-diaza-spiro[2.5]octane(E121)

A mixture of intermediate D29 (0.096 g, 0.347 mmol), D62 (0.092 g, 0.416mmol) and DIPEA (0.121 ml, 0.693 mmol) in CH₃CN (0.5 ml) was heated at180° C. under microwave irradiation for 40 min. After cooling, themixture was concentrated in vacuo. The crude product was purified bycolumn chromatography (silica gel; DCM/EtOAc 100/0 to 60/40 as eluent).The desired fractions were collected and concentrated in vacuo. Thecrude produdt was crystallized from DIPE to yield final compound E121(0.056 g, 38%).

Example 1238-Trifluoromethyl-3-(2′-cyclopropyl)ethyl-7-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(E123)

A mixture of intermediate D64 (0.15 g, 0.518 mmol), phenylpiperidine(0.109 g, 0.673 mmol) and DIPEA (0.316 ml, 1.812 mmol) in CH₃CN (4 ml)was heated in a sealed tube at 95° C. overnight. After cooling,additional phenylpiperidine (0.040 g) was added. The mixture was heatedagain at 95° C. for 4 h and then at r.t. overnight. The precipitate wascollected and washed with CH₃CN and DIPE to yield final compound E123(0.120 g, 56%) as a white solid.

Example 1398-Chloro-3-(2,2,2-trifluoroethyl)-7-(3,3-dimethyl-3H-spiro[benzo[c]furan-1,4′-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(E1139

A mixture of intermediate D67 (0.527 g, 1.059 mmol) andcopper(II)chloride (0.285 g, 2.118 mmol) in DMF (6.6 ml) was heated at50° C. for 1 h. After cooling at r.t., the mixture was concentrated invacuo. The residue was dissolved in EtOAc and washed with NH₄Cl/NH₄OHmixture and water. The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/7M solution of NH₃ in MeOH up to 8% aseluent). The desired fractions were collected and concentrated in vacuoto yield final compound E139 (0.156 g, 32%).

Example 1453-Cyclopropylmethyl-8-methyl-7-(4-phenyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(E145)

To a stirred solution of intermediate D71 (0.14 mg, 0.632 mmol) intoluene (6 ml) were added phenylpiperidine (0.132 g, 0.821 mmol),palladium(II)acetate (7.15 mg, 0.0316 mmol), tert-BuONa (0.091 g, 0.947mmol) and BINAP (0.029 g, 0.047 mmol) and the reaction mixture washeated in a sealed tube at 100° C. for 24 h. After cooling, the reactionmixture was refilled with additional amount of phenylpiperidine (20 mg),palladium(II)acetate (7.15 mg), tert-BuONa (30 mg) and BINAP (30 mg) andheated at 100° C. overnight. After cooling, the mixture was diluted withEtOAc and washed with water. The organic layer was separated, dried(Na₂SO₄) and concentrated in vacuo. The crude product was purified bycolumn chromatography (silica gel; DCM/EtOAc 100/0 to 100/0, then DCM/7Msolution of NH₃ in MeOH up to 3% as eluent). The desired fractions werecollected and concentrated in vacuo to a residue that was trituratedwith DIPE to yield final compound E145 (0.15 g, 69%).

Example 1471′-[3-cyclopropylmethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]-3,3-difluoro-3H-spiro[benzo[c]furan-1,4′-piperidine](E147)

A mixture of intermediate D29 (0.159 g, 0.577 mmol), intermediate D74(0.13 g, 0.577 mmol) and DIPEA (0.298 g, 2.31 mmol) in CH₃CN (3 ml) washeated at 120° C. for 24 h. After cooling, the solvent was concentratedin vacuo. The residue was dissolved in DCM and washed with Na₂CO₃ (10%aqueous solution). The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by HPLC to yieldfinal compound E147 (0.058 g, 21.6%).

Example 1488-Trifluoromethyl-3-(cyclopropylmethyl)-7-(4-methyl-4-(2-pyridinyl)-piperidin-1-yl)-1,2,4-triazolo[4,3-a]pyridine(E148)

A mixture of intermediate D29 (0.150 g, 0.544 mmol), D78 (0.169 g, 0.816mmol) and DIPEA (0.237 ml, 1.36 mmol) in CH₃CN (5 ml) was heated at 180°C. under microwave irradiation for 45 min. After cooling, the mixturewas concentrated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/MeOH 95/5 as eluent). The desiredfractions were collected and concentrated in vacuo. The crude productwas treated with DIPE to yield final compound E148 (0.085 g, 37.6%) as acream solid.

Example 1538-Trifluoromethyl-3-(2-pyridinylmethyl)-7-(4-phenylpiperidin-1-yl)-1,2,4-triazolo[4,3a]pyridine(E153)

A mixture of intermediate D80 (0.18 g, 0.576 mmol), phenylpiperidine(0.111 g, 0.691 mmol) and DIPEA (0.201 ml, 1.151 mmol) in CH₃CN (5 ml)was heated at 180° C. under microwave irradiation for 20 min. Aftercooling, the reaction mixture was refilled with additionalphenylpiperidine (0.5 eq.) and DIPEA (0.1 ml) and heated at 180° C.under microwave irradiation for 20 min. After cooling, the mixture wasconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/MeOH as eluent). The desired fractionswere collected and concentrated in vacuo. The crude product wastriturated with Et₂O to yield final compound E153 (0.11 g, 44%)

Example 1713-Cyclopropylmethyl-8-ethyl-7-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(E171)

To a stirred solution of intermediate D81 (0.05 mg, 0.212 mmol) intoluene (3 ml) were added phenylpiperidine (0.044 g, 0.276 mmol),palladium(II)acetate (2.4 mg, 0.0106 mmol), tert-BuONa (0.031 g, 0.318mmol) and BINAP (9.9 g, 0.016 mmol) and the reaction mixture was heatedin a sealed tube at 100° C. for 24 h. After cooling, the mixture wasdiluted with EtOAc and washed with water. The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by column chromatography (silica gel; DCM/MeOH from 100/0to 92/8 as eluent). The desired fractions were collected andconcentrated in vacuo to a residue that was triturated with DIPE toyield final compound E171 (0.042 g, 55%) as an off-white solid.

Example 1593-Cyclopropylmethyl-8-cyclopropyl-7-(4-phenylpiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(E159)

To a stirred solution of intermediate D82 (0.07 mg, 0.283 mmol) intoluene (3 ml) were added phenylpiperidine (0.059 g, 0.367 mmol),palladium(II)acetate (3.2 mg, 0.014 mmol), tert-BuONa (0.041 g, 0.424mmol) and BINAP (13.2 g, 0.0212 mmol) and the reaction mixture washeated in a sealed tube at 100° C. for 24 h. After cooling, the mixturewas diluted with EtOAc and washed with water. The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by column chromatography (silica gel; DCM/MeOH from 100/0to 95/5 as eluent). The desired fractions were collected andconcentrated in vacuo to a residue that was triturated with DIPE toyield final compound E159 (0.060 g, 57%) as a white solid.

Example 1823-(Cyclopropylmethyl)-7-((3R)-4-3,5-difluorophenyl-3-methylpiperazin-1-yl)-(8-trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine(E182)

A mixture of intermediate D29 (0.100 g, 0.363 mmol),(R)-1-(3,5-difluorophenyl)-2-methylpiperazine [C.A.S.845740-74-1] (0.137g, 0.472 mmol) and DIPEA (0.126 ml, 0.726 mmol) in CH₃CN (1 ml) washeated at 180° C. under microwave irradiation for 40 min. After cooling,the reaction mixture was refilled with(R)-1-(3,5-difluorophenyl)-2-methylpiperazine (1 eq.) and then heated at180° C. under microwave irradiation for 1 hour. After cooling, themixture was concentrated in vacuo. The crude product was purified bycolumn chromatography (silica gel; DCM/EtOAc from 100/0 to 60/40 aseluent). The desired fractions were collected and concentrated in vacuoto yield final compound E182 (0.021 g, 13%). Optical rotation −131.7°(589 nm, c 0.63 w/v %, DMF, 20° C.)

Example 2001′-[3-(Cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-5-fluoro-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine](E200)

A mixture of intermediate D29 (0.179 g, 0.649 mmol), intermediate D85(0.168 g, 0.714 mmol) and DIPEA (0.396 ml, 2.272 mmol) in CH₃CN (3 ml)was heated at 195° C. overnight. After cooling, the precipitate wasfiltered off and washed with CH₃CN. The filtrate was concentrated invacuo. The crude product was purified by column chromatography (silicagel; DCM/MeOH from 100/0 to 97/3 as eluent). The desired fractions werecollected and concentrated in vacuo to give a residue that wastriturated with Et₂O to yield final compound E200 (0.135 g, 61%).

Example 268-Chloro-3-cyclopropylmethyl-7-[4-phenyl-piperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine(E26)

To a stirred solution of intermediate D13 (0.2 g, 0.6 mmol) in toluene(9.5 ml) were added phenylpiperidine (0.125 g, 0.78 mmol),palladium(II)acetate (6.8 mg, 0.03 mmol), Cs₂CO₃ (0.391 g, 1.2 mmol) andBINAP (0.028 g, 0.045 mmol) and the reaction mixture was heated at 120°C. for 16 h in a sealed tube. After cooling, the mixture was filteredthrough a pad of diatomaceous earth. The filtrate was concentrated invacuo. The residue was purified again by column chromatography (silicagel; DCM/MeOH from 100/0 to 80/20 as eluent). The desired fractions werecollected and concentrated in vacuo to yield final compound E26 (0.135g, 61%).

Example 2078-Bromo-3-cyclopropylmethyl-7-[4-phenylpiperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine(E207)

To a stirred solution of intermediate D86 (0.08 g, 0.241 mmol) in DCM (4ml) was added N-bromosuccinimide (0.051 g, 0.289 mmol). The resultingmixture was stirred at r.t. for 40 min. The mixture was carefully washedwith NaHCO₃ (aqueous sat. solution) and extracted with DCM. The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM/EtOAcfrom 100/0 to 73/27 as eluent). The desired fractions were collected andconcentrated in vacuo to a residue that was triturated with Et₂O toyield final compound E207 (0.055 g, 56%).

Example 2243-(Cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine(E224)

To a solution of 1-(2,4-difluorophenyl)piperazine [C.A.S. 115761-79-0](0.088 g, 0.446 mmol) in DCE (2.14 ml) stirred at r.t. was added D88(0.1 g, 0.371 mmol) and the resulting mixture was stirred at r.t.overnight. Then, acetic acid (0.037 ml) was added and stirred at r.t.for 4 h more. Then, sodium triacetoxy-borohydride (0.87 g, 0.409 mmol)was added and stirred at r.t. overnight. The reaction mixture wasneutralized with Na₂CO₃ (aqueous sat. solution) and extracted with DCM.The organic layer was dried (Na₂SO₄) and concentrated in vacuo. Thecrude product thus obtained was purified by column chromatography(silica gel; DCM/EtOAc from 100/0 to 50/50 as eluent). The desiredfractions were collected and concentrated in vacuo. The residue obtainedwas triturated with DIPE to yield final compound E224 (0.107 g, 64%).

Example 2443-cyclopropylmethyl-7-[1-(4-phenyl-1-piperidinyl)ethyl]-8-trifluoromethyl-1,2,4-triazolo[4,3-a]pyridine(E244)

A mixture of D92 (0.095 g, 0.216 mmol), phenylpiperidine (0.035 g, 0.216mmol) and K₂CO₃ (0.06 g, 0.431 mmol) in CH₃CN (4.9 ml) was heated in asealed tube at 85° C. for 5 days. After cooling, the mixture wasfiltered through a pad of diatomaceous earth and washed with EtOAc. Thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography (silica gel; DCM/EtOAc from 100/0 to 50/50 as eluent).The desired fractions were collected and concentrated in vacuo. Theresidue thus obtained was triturated with DIPE to yield final compoundE244 (0.035 g, 32%).

Example 2503-(Cyclopropylmethyl)-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine(E250)

To a solution of 4-fluoro-4-phenylpiperidine hydrochloride [C.A.S.1056382-25-2] (0.096 g, 0.446 mmol) in DCE stirred at r.t. (2.14 ml) wasadded D88 (0.1 g, 0.371 mmol) and the resulting mixture was stirred atr.t. overnight. Then, acetic acid (0.037 ml) was added and stirred atr.t. for 4 h. Then, sodium triacetoxy-borohydride (0.87 g, 0.409 mmol)was added and stirred at r.t. overnight. The reaction mixture wasneutralized with Na₂CO₃ (aqueous sat. solution) and extracted with DCM.The organic layer was dried (Na₂SO₄) and concentrated in vacuo. Thecrude product thus obtained was purified by column chromatography(silica gel; DCM/EtOAc from 100/0 to 50/50 as eluent). The desiredfractions were collected and concentrated in vacuo. The residue obtainedwas triturated with Et₂O to yield final compound E250 (0.029 g, 18%).

Example 2983-(Cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine(E298)

Method A

D90 (0.4 g, 0.9 mmol) was added to a stirred solution ofphenylpiperidine (0.174 mg, 1.08 mmol) and DIPEA (0.233 ml, 1.35 mmol)in CH₃CN (10 ml). The resulting mixture was heated in a sealed tube at100° C. for 4 h. The resulting mixture was concentrated in vacuo. Theresidue was purified by column chromatography (silica gel; DCM/EtOAcfrom 100/0 to 50/50 as eluent). The desired fractions were collected andconcentrated in vacuo. The residue thus obtained was triturated withDIPE to yield final compound E298 (0.272 g, 77%) as a white solid.

Method B

To a mixture of compound D29 (0.120 g, 0.435 mmol), potassiumtrifluoro[(4-phenyl-1-piperidinyl)methyl]-borate(1-) (1:1) [C.A.S.1152617-06-5] (0.367 g, 1.306 mmol) in THF (4 ml) and water (0.4 ml)under a nitrogen atmosphere were added2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl X-Phos(12.45 mg, 0.026 mmol), palladium(II)acetate (2.93 mg, 0.013 mmol) andCs₂CO₃ (0.426 g, 1.306 mmol). The reaction mixture was heated at 80° C.for 3 days and at r.t. for 2 days. The mixture was washed with water andextracted with EtOAc. The organic layer was separated and concentratedin vacuo. The residue was purified by manifold (Sep-Pak® silicacartridge; DCM/acetone from 100/0 to 90/10 as eluent) followed by columnchromatography (silica gel; DCM/EtOAc from 100/0 to 80/20 as eluent).The desired fractions were collected and concentrated in vacuo to aresidue that was triturated with DIPE to yield final compound E298(0.065 g, 25%).

Example 2143-(Cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridinehydrochloride salt (E214)

To a stirred solution of final compound E298 (0.065 g, 0.156 mmol) inMeOH (0.25 ml) and 1,4-dioxane (3.76 ml) was added dropwise HCl (4M in1,4-dioxane, few drops). The resulting suspension was concentrated invacuo. The solid residue was triturated with acetone, filtered and driedin vacuo to yield final compound E214 (0.061 g, 82%).

Example 2828-Chloro-3-cyclopropylmethyl-7-[(4-(2,6-difluorophenyl-1-piperazinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine(E282)

D96 (0.1 g, 0.39 mmol) was added to a stirred solution of1-(2,6-difluorophenyl)-piperazine (0.96 mg, 0.429 mmol) and DIPEA (0.094ml, 0.547 mmol) in CH₃CN (2 ml). The resulting mixture was heated in asealed tube at 100° C. for 4 h. The resulting mixture was concentratedin vacuo. The residue was purified by column chromatography (silica gel;DCM/7M solution of NH₃ in MeOH up to 4% as eluent). The desiredfractions were collected and concentrated in vacuo. The residue thusobtained was triturated with DIPE to yield final compound E282 (0.1 g,61%) as an off white solid.

Example 2068-Cyano-3-(4-pyridinyl)-7-[4-phenylpiperidin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine(E206)

A suspension of D97 (0.234 mg, 0.612 mmol), 4-pyridinyl boronic acid(0.113 g, 0.918 mmol) and Pd(PPh₃)₄ (0.035 g, 0.031 mmol) in NaHCO₃,(1.5 ml, aqueous sat. solution) and 1,4-dioxane (3 ml) was heated at150° C. under microwave irradiation for 10 min. After cooling, themixture was refilled with additional pyridinyl-4-boronic acid (0.050 g)and Pd(PPh₃)₄ (0.020 g). The mixture was heated at 150° C. undermicrowave irradiation for 10 min. After cooling to r.t. the mixture wasfiltered through a pad of diatomaceous earth and washed with DCM. Thefiltrate was collected, dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by column chromatography (silica gel;DCM/EtOAc 100/0 to 70/30 as eluent). The desired fractions werecollected and concentrated in vacuo to give a residue that wastriturated with Et₂O to yield final compound E206 (0.055 g, 24%) as ayellow solid.

Example 2043-Cyclopropylmethyl-7-[1-(2,4-difluoro-phenyl)-piperidin-4-yl]-8-methyl-[1,2,4]triazolo[4,3-a]pyridine(E204)

To a stirred solution of intermediate D101 (0.148 mg, 0.546 mmol) intoluene (7 ml) were added 1-bromo-2,4-difluorobenzene (0.068 g, 0.6mmol), palladium(II)acetate (6.2 mg, 0.0273 mmol), tert-BuONa (0.105 g,1.092 mmol) and BINAP (0.034 g, 0.055 mmol) and the reaction mixture washeated in a sealed tube at 85° C. for two days. After cooling, themixture was diluted with EtOAc and filtered through a pad ofdiatomaceous earth. The filtrate was washed with water and NaCl (aqueoussat. solution). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel; DCM/7M solution of NH₃ in MeOH up to 5% aseluent). The desired fractions were collected and concentrated in vacuoto a residue that was crystallized from Et₂O to yield final compoundE204 (0.053 g, 25.4%).

Table 1 below lists compounds of Formula (I), which were preparedaccording to the above examples.

TABLE 1 Compounds prepared according to Formula (I).

  Co. no.   Exp. no.     R¹     R²    

Stereochem./Salt Form/Optical Rotation (OR)  1 E1*

 2 E2*

 3 E3*

 4 E4*

 5 E5*

 6 E6*

 7 E7*

 8 E8*

 9 E9*

 10 E10*

 11 E11*

 12 E12*

 13 E13

 14 E14*

 15 E15

 16 E16

 17 E17

 18 E18

 19 E10

 20 E2

 21 E10

 22 E1

 23 E1

 24 E1

 25 E10

 26 E26*; E1

 27 E1

 28 E13

 29 E1

 30 E1

 31 E1

 32 E1

 33 E1

 34 E1

 35 E1

 36 E12

 37 E12

 38 E1

 39 E1

 40 E13

 41 E2

 42 E2

 43 E1

 44 E13

cis  45 E13

trans  46 E1

 47 E1

 48 E1

 49 E13

trans  50 E13

cis  51 E13

 52 E13

 53 E1

 54 E13

 55 E13

 56 E2

 57 E1

 58 E13

cis  59 E2

 60 E13

 61 E1

 62 E1

 63 E1

 64 E1

 65 E1

 66 E1

 67 E1

 68 E2

 69 E13

 70 E6

 71 E1

 72 E2

 73 E13

trans  74 E1

 75 E2

rac-(2aα,3α,3aα)  76 E13

 77 E13

 78 E13

 79 E13

 80 E2

 81 E1

rac-(2aα,3α,3aα)  82 E6

 83 E6

 84 E6

 85 E6

 86 E6

 87 E1

 88 E6

 89 E13

 90 E13

 91 E13

 92 E13

 93 E6

 94 E1

 95 E6

 96 E6

trans  97 E1

 98 E1

 99 E6

100 E100*

101 E1

102 E6

103 E6

104 E6

105 E6

106 E6

107 E6

108 E6

•1HCl •1.5H₂O 109 E13

110 E13

111 E13

112 E112*

113 E13

114 E2

115 E6

116 E6

117 E6

118 E13

119 E119*

120 E13

121 E121*; E13

122 E13

123 E123*

124 E13

125 E6

126 E6

127 E6

128 E13

OR: −131.1° (589 nm, c 0.52 w/v %, DMF, 20° C.) 129 E13

130 E13

131 E13

OR: −132° (589 nm, c 0.52 w/v %, DMF, 20° C.) 132 E13

133 E6

134 E13

135 E6

136 E13

137 E13

138 E1

139 E139*, E1

140 E6

141 E13

142 E13

143 E6

144 E145

145 E145*

146 E6

147 E147*

148 E148*

149 E6

150 E13

151 E13

152 E13

S 153 E153*, E13

154 E6

155 E13

156 E6

157 E6

158 E6

159 E159*

160 E6

161 E6

162 E13

163 E6

164 E6

165 E13

166 E13

cis 167 E13

168 E6

169 E13

170 E6

171 E171*

172 E6

173 E6

174 E13

175 E13

176 E6

177 E13

178 E6

179 E6

180 E13

S-enantiomer OR: −138.4° (589 nm, c 0.51 w/v %, DMF, 20° C.) 181 E6

S-enantiomer OR: 26.2° (589 nm, c 0.52 w/v %, DMF, 20° C.) 182 E182*

R-enantiomer OR: −131.7° (589 nm, c 0.63 w/v %, DMF, 20° C.) 183 E13

184 E6

R-enantiomer OR: −28.6° (589 nm, c 0.53 w/v %, DMF, 20° C.) 185 E13

186 E6

cis 187 E6

188 E212

189 E13

190 E6

191 E1

S-enantiomer OR: 63.4° (589 nm, c 0.54 w/v %, DMF, 20° C.) 192 E1

R-enantiomer 193 E13

194 E13

195 E13

196 E13

197 E13

198 E13

199 E13

200 E200*

201 E13

202 E13

203 E13

204 E204*

205 E206

206 E206*

207 E207*

208 E6

cis-a OR: −93.1° (589 nm, c 0.55 w/v %, MeOH, 20° C.) 209 E13

cis-a OR: −226° (589 nM, c 0.59 w/v %, MeOH, 20° C.) 210 E6

211 E6

cis-b OR: 112.5° (589 nm, c 0.59 w/v %, MeOH, 20° C.) 212 E13

cis-b OR: 229° (589 nm, c 0.58 w/v %, MeOH, 20° C.) 213 E6

214 E214*; E298 6-A

•1.8HCl 215 E6

216 E13

217 E6

•1HCl 218 E6

219 E232

220 E232

221 E224

222 E6

223 E6

cis 224 E224*

225 E224

226 E224

227 E13

228 E6

229 E224

230 E224

231 E13

232 E224

233 E13

234 E224

235 E224

236 E13

237 E224

238 E13

239 E224

240 E224

241 E224

242 E6

243 E224

244 E244*

245 E224

246 E224

247 E224

248 E224

249 E224

250 E250*

251 E298- A

252 E224

253 E224

254 E224

255 E224

256 E224

257 E224

258 E224

259 E224

260 E198- A

261 E224

262 E224

263 E298- A

264 E224

265 E298- A

266 E298- A

rac(2aα,3α,3aα) 267 E298- A

268 E298- A

269 E298- A

270 E282

271 E281

272 E282

273 E282

274 E298- A

275 E298- A

276 E298- A

277 E298- A

278 E298- A

279 E298- A

280 E6

281 E282

282 E282*

283 E282

284 E282

285 E282

286 E282

287 E298- A

288 E282

289 E282

290 E282

rac(2aα,3α,3aα) 291 E1

292 E224

—Cl

293 E6

—Cl

294 E224

—Cl

295 E250

—Cl

296 E298- A

—CF₃

297 E297*

—CF₃

•1.1HCl 298 E298*

—CF₃

299 E282

—Cl

300 E282

—Cl

301 E298- A

—CF₃

302 E282

—Cl

303 E282

—Cl

304 E6

—Cl

305 E13

—CF₃

306 E13

—CF₃

307 E224

—Cl

308 E13

—CF₃

309 E6

—Cl

310 E6

—Cl

311 E1

—Cl

312 E1

—Cl

313 E282

—Cl

314 E282

—Cl

315 E298- A

—CF₃

316 E250

317 E250

318 E250

319 E250

—CF₃

320 E250

—CF₃

321 E250

—CF₃

322 E250

—CF₃

323 E250

—CF₃

324 E250

—CF₃

325 E250

—CF₃

326 E250

—CF₃

327 E250

—CF₃

328 E250

—CF₃

329 E250

—CF₃

330 E250

—CF₃

331 E298- A

332 E298- A

333 E6

334 E250

—CF₃

rac-(2aα,3α,3aα) 335 E250

—CH₃

rac-(2aα,3α,3aα) 336 E250

—CF₃

337 E250

—CF₃

rac-(2aα,3α,3aα) 338 E250

—CF₃

rac-(2aα,3α,3aα) 339 E250

—CF₃

•HCl 340 E250

—CF₃

•HCl 341 E250

—CF₃

342 E250

—CF₃

343

—CF₃

•HCl 344 E250

—CF₃

345 E250

—CF₃

rac-(2aα,3α,3aα) 346 E250

—CF₃

347 E250

—CF₃

348 E250

—CH₃

349 E250

—CF₃

350 E250

—CF₃

rac-(2aα,3α,3aα) 351 E250

—CF₃

352 E250

—CF₃

353 E250

—CF₃

354 E250

—CF₃

355 E250

—CF₃

356 E250

—CF₃

357 E250

—Cl

358 E207

—Br

359 E250

—CF₃

360 E250

—CF₃

361 E250

—CF₃

362 E250

—CF₃

363 E250

—Cl

364 E250

—Cl

365 E250

—CF₃

366 E250

—CF₃

367 E250

—CF₃

368 E250

—Cl

*means exemplified compounds in the experimental section. Whenever cis-or trans-stereochemistry is indicated, it denotes that it is, whereapplicable, a mixture of all possible cis- or trans-stereoisomericforms, in particular, a racemic mixture, unless otherwise indicated.When the mixture was separated, the different forms are denoted, forexample, cis-a and cis-b.

C. Analytical Part Melting Points

Values are peak values, and are obtained with experimental uncertaintiesthat are commonly associated with this analytical method. For a numberof compounds, melting points were determined in open capillary tubeseither on a Mettler FP62 or on a Mettler FP81HT-FP90 apparatus. Meltingpoints were measured with a temperature gradient of 10° C./min. Maximumtemperature was 300° C. The melting point was read from a digitaldisplay.

Optical Rotation

Values were measured on a Perkin-Elmer 341 polarimeter with a sodiumlamp and reported as follows: [α]_(l) ^(t°C) (c g/100 ml, solvent).

LCMS

For LCMS characterization of the compounds of the present invention, thefollowing methods were used.

General Procedure A (for Waters Ms Instruments)

The HPLC measurement was performed using an HP 1100 (AgilentTechnologies) system comprising a pump (quaternary or binary) withdegasser, an autosampler, a column oven, a DAD and a column as specifiedin the respective methods below. Flow from the column was split to theMS spectrometer. The MS detector was configured with either an ESionization source or an ESCI dual ionization source (ES combined withatmospheric pressure CI). Nitrogen was used as the nebulizer gas. Thesource temperature was maintained at 140° C. Data acquisition wasperformed with MassLynx-Openlynx software.

General Procedure B (for Agilent MS Instrument (MSD))

The HPLC measurement was performed using an HP 1100 (AgilentTechnologies) system comprising a binary pump with degasser, anautosampler, a column oven, a DAD and a column as specified in therespective methods below. Flow from the column was split to a MSspectrometer. The MS detector was configured with an ESCI dualionization source (ES combined with atmospheric pressure CI). Nitrogenwas used as the nebulizer gas. The source temperature was maintained at100° C. Data acquisition was performed with Chemsation-Agilent DataBrowser software.

General Procedure C (for Waters MS Instruments (Acquity SQD))

The UPLC (Ultra Performance Liquid Chromatography) measurement wasperformed using an Acquity UPLC (Waters) system comprising a samplerorganizer, a binary pump with degasser, a four column's oven, a DAD anda column as specified in the respective methods below. Column flow wasused without split to the MS detector. The MS detector was configuredwith an ESCI dual ionization source (ES combined with atmosphericpressure CI). Nitrogen was used as the nebulizer gas. The sourcetemperature was maintained at 140° C. Data acquisition was performedwith MassLynx-Openlynx software.

Method 1

In addition to the general procedure B: Reversed phase HPLC was carriedout on an XDB-C18 cartridge (1.8 μm, 2.1×30 mm) from Agilent, at 60° C.with a flow rate of 1 ml/min, at 60° C. The gradient conditions usedare: 90% A (0.5 g/l NH₄Ac solution), 5% B (CH₃CN), 5% C (MeOH) to 50% Band 50% C in 6.5 min, to 100% B at 7 min and equilibrated to initialconditions at 7.5 min until 9.0 min. Injection volume 2 μl. HRMS (TOFdetector) were acquired only in positive ionization mode by scanningfrom 100 to 750 in 0.5 s using a dwell time of 0.1 s. The capillaryneedle voltage was 2.5 kV and the cone voltage was 20 V.Leucine-Enkephaline was the standard substance used for the lock masscalibration.

Method 2

In addition to the general procedure A: Reversed phase HPLC was carriedout on a Sunfire-C18 column (2.5 μm, 2.1×30 mm) from Waters, with a flowrate of 1.0 ml/min, at 60° C. The gradient conditions used are: 95% A(0.5 g/l NH₄Ac solution+5% of CH₃CN), 2.5% B (CH₃CN), 2.5% C (MeOH) to50% B, 50% C in 6.5 min, kept till 7.0 min and equilibrated to initialconditions at 7.3 min until 9.0 min. Injection volume 2 μl. HRMS (TOFdetector) were acquired by scanning from 100 to 750 in 0.5 using a dwelltime of 0.3 s. The capillary needle voltage was 2.5 kV for positiveionization mode and 2.9 kV for negative ionization mode. The conevoltage was 20 V for both positive and negative ionization modes.Leucine-Enkephaline was the standard substance used for the lock masscalibration.

Method 3

In addition to the general procedure A: Reversed phase HPLC was carriedout on a Sunfire-C18 column (2.5 μm, 2.1×30 mm) from Waters, with a flowrate of 1.0 ml/min, at 60° C. The gradient conditions used are: 95% A(0.5 g/l NH₄Ac solution+5% of CH₃CN), 5% B (CH₃CN) to 100% B in 6.5 min,kept till 7.0 min and equilibrated to initial conditions at 7.3 minuntil 9.0 min. Injection volume 2 μA HRMS (TOF detector) were acquiredby scanning from 100 to 750 in 0.5 s using a dwell time of 0.3 s. Thecapillary needle voltage was 2.5 kV for positive ionization mode and 2.9kV for negative ionization mode. The cone voltage was 20 V for bothpositive and negative ionization modes. Leucine-Enkephaline was thestandard substance used for the lock mass calibration.

Method 4

In addition to the general procedure A: Reversed phase HPLC was carriedout on a Sunfire-C18 column (2.5 μm, 2.1×30 mm) from Waters, with a flowrate of 1.0 ml/min, at 60° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l NH₄Ac solution+5% CH₃CN),5% B (mixture of CH₃CN/MeOH, 1/1), to 100% B in 5.0 min, kept till 5.15min and equilibrated to initial conditions at 5.30 min until 7.0 min.Injection volume 2 LRMS (single quadrupole, SQD detector) were acquiredin positive ionization mode by scanning from 100 to 1000 in 0.1 s usingan inter-channel delay of 0.08 s. The capillary needle voltage was 3 kV.The cone voltage was 20 V and 50 V for positive ionization mode and 30Vfor negative ionization mode.

Method 5

In addition to the general procedure A: Reversed phase HPLC was carriedout on a Sunfire-C18 column (2.5 μm, 2.1×30 mm) from Waters, with a flowrate of 1.0 ml/min, at 60° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l NH₄Ac solution+5% CH₃CN),5% B (mixture of CH₃CN/MeOH, 1/1), to 100% B at 6.5 min, kept till 7.0min and equilibrated to initial conditions at 7.3 min until 9.0 min.Injection volume 2 μl. LRMS (single quadrupole, SQD detector) wereacquired by scanning from 100 to 1000 in 0.1 s using an inter-channeldelay of 0.08 s. The capillary needle voltage was 3 kV. The cone voltagewas 20 V for positive ionization mode and 30 V for negative ionizationmode.

Method 6

In addition to the general procedure A: Reversed phase HPLC was carriedout on a XBridge-C18 column (2.5 μm, 2.1×30 mm) from Waters, with a flowrate of 1.0 ml/min, at 60° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l NH₄Ac solution+5% CH₃CN),5% B (mixture of CH₃CN/MeOH, 1/1), to 100% B in 6.5 min, kept till 7.0min and equilibrated to initial conditions at 7.3 min until 9.0 min.Injection volume 2 μl. LRMS (single quadrupole, SQD detector) wereacquired by scanning from 100 to 1000 in 0.1 s using an inter-channeldelay of 0.08 second. The capillary needle voltage was 3 kV. The conevoltage was 20 V for positive ionization mode and 30 V for negativeionization mode.

Method 7

In addition to the general procedure B: Reversed phase HPLC was carriedout on an Eclipse Plus-C18 column (3.5 μM, 2.1×30 mm) from Agilent, witha flow rate of 1.0 ml/min, at 60° C. without split to the MS detector.The gradient conditions used are: 95% A (0.5 g/l NH₄Ac solution+5%CH₃CN), 5% B (mixture of CH₃CN/MeOH, 1/1), to 100% B in 5.0 min, kepttill 5.15 min and equilibrated to initial conditions at 5.30 min until7.0 min. Injection volume 2 μl. LRMS (single quadrupole, SQD detector)were acquired by scanning from 100 to 1000 in 0.1 second using aninter-channel delay of 0.08 second. The capillary needle voltage was 3kV. The cone voltage was 20 V for positive ionization mode and 30 V fornegative ionization mode.

Method 8

In addition to the general procedure B: Reversed phase HPLC was carriedout on an Eclipse Plus-C18 column (3.5 μM, 2.1×30 mm) from Agilent, witha flow rate of 1.0 ml/min, at 60° C. without split to the MS detector.The gradient conditions used are: 95% A (0.5 g/l NH₄Ac solution+5%CH₃CN), 5% B (mixture of CH₃CN/MeOH, 1/1), to 100% B at 6.5 min, kepttill 7.0 min and equilibrated to initial conditions at 7.3 min until 9.0min. Injection volume 2 μl. LRMS (single quadrupole, SQD detector) wereacquired by scanning from 100 to 1000 in 0.1 s using an inter-channeldelay of 0.08 s. The capillary needle voltage was 3 kV. The cone voltagewas 20 V for positive ionization mode and 30 V for negative ionizationmode.

Method 9

In addition to the general procedure B: Reversed phase HPLC was carriedout on an Eclipse Plus-C18 column (3.5 μm, 2.1×30 mm) from Agilent, witha flow rate of 1.0 ml/min, at 60° C. without split to the MS detector.The gradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% CH₃CN), 5% B (CH₃CN), to 100% B at 6.5 minutes, kept till7.0 minutes and equilibrated to initial conditions at 7.3 minutes until9.0 minutes. Injection volume 2 μl. Low-resolution mass spectra (singlequadrupole, SQD detector) were acquired by scanning from 100 to 1000 in0.1 seconds using an inter-channel delay of 0.08 second. The capillaryneedle voltage was 3 kV. The cone voltage was 20 V for positiveionization mode and 30 V for negative ionization mode.

Method 10

In addition to the general procedure C: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 0.8 ml/min, at 60° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l NH₄Ac solution+5% CH₃CN),5% B (mixture of CH₃CN/MeOH, 1/1), to 20% A, 80% B in 6.3 min, to 100% Bin 6.85 min, kept till 7.50 min and equilibrated to initial conditionsat 7.75 min until 9.0 min. Injection volume 0.5 μl. LRMS (singlequadrupole, SQD detector) were acquired by scanning from 100 to 1000 in0.1 s using an inter-channel delay of 0.08 second. The capillary needlevoltage was 3 kV. The cone voltage was 20 V for positive ionization modeand 30 V for negative ionization mode.

Method 11

In addition to the general procedure C: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 0.8 ml/min, at 60° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l NH₄Ac solution+5% CH₃CN),5% B (mixture of CH₃CN/MeOH, 1/1), to 20% A, 80% B in 4.9 min, to 100% Bin 5.3 min, kept till 5.8 min and equilibrated to initial conditions at6.0 min until 7.0 min. Injection volume 0.5 μl. LRMS (single quadrupole,SQD detector) were acquired by scanning from 100 to 1000 in 0.1 s usingan inter-channel delay of 0.08 second. The capillary needle voltage was3 kV. The cone voltage was 20 V for positive ionization mode and 30 Vfor negative ionization mode.

Method 12

In addition to the general procedure C: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 1.0 ml/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% CH₃CN), 5% B (CH₃CN), to 40% A, 60% B in 4.4 minutes, to 5%A, 95% B in 5.6 minutes, kept till 5.8 minutes and equilibrated toinitial conditions at 6.0 minutes until 7.0 minutes. Injection volume0.5 μl. Low-resolution mass spectra (single quadrupole, SQD detector)were acquired by scanning from 100 to 1000 in 0.1 seconds using aninter-channel delay of 0.08 second. The capillary needle voltage was 3kV. The cone voltage was 25 V for positive ionization mode and 30 V fornegative ionization mode.

Method 13

In addition to the general procedure C: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 1.0 ml/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B in 2.8minutes, to 5% A, 95% B in 3.6 minutes, kept till 3.8 minutes andequilibrated to initial conditions at 4.0 minutes until 5.0 minutes.Injection volume 0.5 μl. Low-resolution mass spectra (single quadrupole,SQD detector) were acquired by scanning from 100 to 1000 in 0.1 secondsusing an inter-channel delay of 0.08 second. The capillary needlevoltage was 3 kV. The cone voltage was 25 V for positive ionization modeand 30 V for negative ionization mode.

Method 14

In addition to the general procedure C: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 1.0 ml/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B in 6.0minutes, to 5% A, 95% B in 7.6 minutes, kept till 7.80 minutes andequilibrated to initial conditions at 8.0 minutes until 9.0 minutes.Injection volume 0.5 μl. Low-resolution mass spectra (single quadrupole,SQD detector) were acquired by scanning from 100 to 1000 in 0.1 secondsusing an inter-channel delay of 0.08 second. The capillary needlevoltage was 3 kV. The cone voltage was 25 V for positive ionization modeand 30 V for negative ionization mode.

Method 15

In addition to the general procedure C: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 1.0 ml/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B in 3.8minutes, to 5% A, 95% B in 4.6 minutes, kept till 5.0 minutes. Injectionvolume 2 μl. Low-resolution mass spectra (single quadrupole, SQDdetector) were acquired by scanning from 100 to 1000 in 0.1 secondsusing an inter-channel delay of 0.08 second. The capillary needlevoltage was 3 kV. The cone voltage was 25 V for positive ionization modeand 30 V for negative ionization mode.

Method 16

In addition to the general procedure C: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 1.0 ml/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B in 7.0minutes, to 5% A, 95% B in 8.6 minutes, kept till 9.0 minutes. Injectionvolume 2 μl. Low-resolution mass spectra (single quadrupole, SQDdetector) were acquired by scanning from 100 to 1000 in 0.1 secondsusing an inter-channel delay of 0.08 second. The capillary needlevoltage was 3 kV. The cone voltage was 25 V for positive ionization modeand 30 V for negative ionization mode.

General Procedure D

The HPLC measurement was performed using an Alliance HT 2790 (Waters)system comprising a quaternary pump with degasser, an autosampler, acolumn oven (set at 40° C., unless otherwise indicated), a DAD and acolumn as specified in the respective methods below. Flow from thecolumn was split to a MS spectrometer. The MS detector was configuredwith an ES ionization source. Mass spectra were acquired by scanningfrom 100 to 1000 in 1 second using a dwell time of 0.1 second. Thecapillary needle voltage was 3 kV and the source temperature wasmaintained at 140° C. Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Wafers-Micromass MassLynx-Openlynx datasystem.

Method 17

In addition to the general procedure D: Column heater was set at 45° C.Reversed phase HPLC was carried out on an Atlantis C18 column (3.5 μm,4.6×100 mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobilephase A: 70% MeOH+30% H₂O; mobile phase B: 0.1% formic acid in H₂O/MeOH95/5) were employed to run a gradient condition from 100% B to 5% B+95%A in 9 min and hold these conditions for 3 min. An injection volume of10 μl was used. Cone voltage was 10 V for positive ionization mode and20 V for negative ionization mode.

Method 18

In addition to the general procedure D: Reversed phase HPLC was carriedout on an Xterra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mMammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile; mobilephase C: methanol) were employed to run a gradient condition from 100% Ato 1% A, 49% B and 50% C in 6.5 minutes, to 1% A and 99% B in 1 minuteand hold these conditions for 1 minute and reequilibrate with 100% A for1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10V for positive ionization mode and 20 V for negative ionization mode.

General Procedure E

The LC measurement was performed using an Acquity UPLC (Waters) systemcomprising a binary pump, a sample organizer, a column heater (set at55° C.), a DAD and a column as specified in the respective methodsbelow. Flow from the column was split to a MS spectrometer. The MSdetector was configured with an ES ionization source. MS were acquiredby scanning from 100 to 1000 in 0.18 s using a dwell time of 0.02 s. Thecapillary needle voltage was 3.5 kV and the source temperature wasmaintained at 140° C. Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

Method 19

In addition to the general procedure E: Reversed phase UPLC was carriedout on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 pin,2.1×50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobilephases (mobile phase A: 0.1% formic acid in H₂O/MeOH 95/5; mobile phaseB: MeOH) were used to run a gradient condition from 95% A and 5% B to 5%A and 95% B in 1.3 min and hold for 0.2 min. An injection volume of 0.5μl was used.

Cone voltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

The results of the analytical measurements are shown in table 2.

TABLE 2 Physico-chemical data for some compounds, retention time (R_(t))in min, [M + H]⁺ peak (protonated molecule), LCMS method and mp (meltingpoint in ° C.). (nd = not determined). Co. No. mp (° C.) [MH⁺] R_(t)(min) LCMS Method 1 181.8 381 4.43 6 2 n.d. 419 8.48 17 3 >300 413 8.2717 4 n.d. 403 3.96 11 5 n.d. 371 4.27 2 6 194.5 395 4.27 5 7 n.d. 4254.12 2 8 >300 423 3.53 3 9 n.d. 369 4.00 3 10 n.d. 332 3.46 2 11 300 4033.71 5 12 n.d. 477 4.21 11 13 n.d. 358 3.88 1 14 n.d. 358 3.94 1 15276.7 435 2.43 12 16 269.1 423 3.03 12 17 >300 429 3.17 12 18 153.7 4373.92 9 19 n.d. 318 3.21 1 20 300 386 3.82 1 21 n.d. 380 3.85 2 22 228.6395 4.64 2 23 n.d. 394 4.14 2 24 n.d. 348 3.62 2 25 227.7 341 4.34 2 26194.1 367 3.69 11 27 n.d. 434 4.19 2 28 >300 346 3.03 11 29 >300 3442.87 11 30 186.1 409 3.79 11 31 237.5 412 3.32 11 32 n.d. 424 4.27 6 33n.d. 368 3.90 6 34 n.d. 372 4.40 2 35 >300 360 3.18 11 36 n.d. 387 4.095 37 n.d. 469 4.88 5 38 203.3 429 3.74 11 39 >300 435 4.05 11 40 n.d.376 2.99 11 41 176.5 403 3.83 11 42 n.d. 385 8.08 17 43 n.d. 401 4.78 544 219 433 3.32 11 45 n.d. 433 3.13 11 46 >300 415 4.03 4 47 n.d. 3682.66 11 48 n.d. 398 3.58 11 49 231.1 395 1.55 11 50 236.1 395 1.93 11 51n.d. 434 3.98 2 52 249.3 505 3.96 4 53 n.d. 401 4.10 9 54 n.d. 404 2.9611 55 n.d. 415 4.72 2 56 230.7 396 3.51 5 57 n.d. 406 3.48 7 58 >300 4613.48 7 59 n.d. 426 3.60 7 60 n.d. 469 3.60 7 61 259 443 3.87 7 62 n.d.486 3.63 7 63 232.2 398 3.15 8 64 n.d. 404 3.38 8 65 n.d. 443 3.70 11 66n.d. 375 4.40 2 67 n.d. 389 4.65 2 68 n.d. 432 3.65 11 69 n.d. 401 3.0411 70 n.d. 493 4.12 11 71 230.7 409 3.95 3 72 n.d. 430 3.80 11 73 n.d.461 3.36 7 74 n.d. 360 3.5 3 75 >300 399 3.28 12 76 >300 402 3.03 12 77n.d. 429 3.15 12 78 231.1 402 1.7 13 79 207.9 445 3.33 12 80 131 4493.98 9 81 >300 393 3.61 9 82 n.d. 401 3.3 12 83 n.d. 419 3.34 12 84 n.d.437 3.4 12 85 n.d. 437 3.51 12 86 n.d. 437 3.37 12 87 >300 417 3.13 1288 255.7 383 2.89 12 89 231.7 403 2.85 12 90 n.d. 434 2.46 12 91 n.d.432 2.69 12 92 n.d. 433 2.45 12 93 235.8 383 4.26 2 94 n.d. 439 3.16 1295 247.2 392 2.96 12 96 144.4 422 2.83 12 97 >300 432 3.1 12 98 269.1423 3.03 12 99 >300 368 2.79 12 100 260.2 424 3.36 12 101 249.5 396 2.8412 102 252.4 369 2.6 12 103 >300 400 3.18 12 104 235.4 423 8.5 17105 >300 396 3.29 12 106 209.43 401 1.41 19 107 229.43 411 6.13 18 108n.d. 413 1.42 19 109 n.d. 447 1.43 19 110 239.9 435 1.43 19 111 n.d. 4332.23 12 112 207.7 457 8.47 17 113 208.72 445 8.38 17 114 175.7 412 2.6712 115 183.8 457 3.4 12 116 232.1 453 3.49 12 117 250.4 453 3.48 12118 >300 373 4.2 2 119 n.d. 430 2.11 12 120 232.1 426 2.98 12 121 218.4428 3.36 12 122 145.7 419 3.62 12 123 300 415 4.99 2 124 n.d. 418 4.19 2125 n.d. 396 3.29 2 126 188.3 400 3.09 2 127 128.3 403 4.7 2 128 172.5416 3.16 12 129 202.1 432 3.12 12 130 >300 359 2.66 12 131 234 416 3.2212 132 144.3 422 4.09 2 133 >300 381 3.48 12 134 164.2 436 3.23 12 135125.7 385 3.48 12 136 221.4 405 3.41 12 137 n.d. 373 2.92 12 138 n.d.424 1.73 12 139 n.d. 451 2.54 13 140 n.d. 399 4.36 14 141 195.56 4231.31 19 142 n.d. 453 6.05 18 143 223.95 419 8.39 17 144 100.7 453 3.5512 145 >300 347 3.45 12 146 >300 381 3.56 12 147 n.d. 465 8.44 17148 >300 416 2.72 12 149 229.27 409 7.24 17 150 n.d. 436 2.97 12 151127.4 415 3.59 12 152 166.7 403 2.85 12 153 >300 438 3.22 12 154 >300403 3.58 12 155 137.6 420 3.13 12 156 >300 389 2.27 12 157 162.6 4082.99 12 158 178.9 466 2.62 12 159 >300 373 3.81 12 160 >300 429 4.01 12161 >300 396 2.24 12 162 112.3 450 3.5 12 163 >300 450 3.41 12 164 n.d.424 3.17 12 165 185.5 432 2.18 12 166 137.5 464 2.39 13 167 n.d. 4182.15 12 168 166.2 381 4.52 14 169 182.3 415 3.64 12 170 160.8 384 1.4613 171 >300 361 2.66 13 172 144 398 2 12 173 268.8 353 2.11 13 174 178.3387 2.18 13 175 180.4 416 2.16 13 176 164.1 400 2.19 13 177 235.5 4172.69 13 178 238.8 382 2.03 13 179 147.5 418 2.16 13 180 84.2 452 2.51 13181 281.2 418 2.4 13 182 147.5 452 2.5 13 183 >300 434 2.3 13 184 269.7418 2.41 13 185 >300 415 2.63 13 186 >300 430 2.31 13 187 193.3 415 2.4613 188 n.d. 478 2.59 13 189 >300 406 2.03 13 190 >300 372 1.93 13 191218.2 446 2.48 13 192 n.d. 446 2.48 13 193 160.2 433 2.64 13 194 148.4433 2.59 13 195 >300 437 2.55 13 196 >300 438 2.32 13 197 137.4 433 2.5813 198 201.9 402 1.58 13 199 199 416 1.68 13 200 >300 475 2.69 13201 >300 478 2.64 13 202 >300 492 2.85 13 203 >300 452 2.37 13 204 283.5383 2.4 13 205 n.d. 380 2.16 13 206 n.d. 381 2.24 13 207 281.5 411 2.413 208 187.5 381 9.18 17 209 182.5 415 9.01 17 210 184.5 444 3.59 12 211186.7 381 1.35 19 212 181 415 9.02 17 213 >300 458 2.08 13 214 255.4 4152.75 13 215 n.d. 418 2.01 13 216 n.d. 430 2.11 13 217 n.d. 430 2.11 13218 n.d. 450 2.37 13 219 128 483 2.75 13 220 191.4 471 2.79 13 221 170.5447 2.84 13 222 n.d. 396 1.91 13 223 188.4 442 2.26 13 224 141.5 4523.16 15 225 188 449 3.14 15 226 124.3 413 3.13 15 227 n.d. 452 2.72 15228 189 396 2.02 15 229 >300 388 2.02 15 230 n.d. 430 1.77 15 231 147.8492 2.7 15 232 241.9 492 3.28 15 233 n.d. 466 9.38 17 234 153.4 451 3.5815 235 201.3 417 3.16 15 236 n.d. 438 1.11 19 237 258.7 437 3.07 15238 >300 444 2.26 15 239 163.7 440 3.35 15 240 259.3 418 2.76 15 241203.9 373 2.54 15 242 206.3 410 2.07 15 243 >300 474 3.66 15 244 142.3429 3.61 15 245 259.7 445 3.47 15 246 186.2 446 2.86 15 247 n.d. 474 5.416 248 181.4 447 3.63 15 249 94.5 447 3.57 15 250 179.2 433 3.26 15 251150..4 417 2.39 15 252 >300 418 2.23 15 253 167.2 427 3.23 15 254 209432 2.8 15 255 182.1 395 3.17 15 256 288.1 384 1.81 15 257 120.4 4133.15 15 258 251.8 393 2.86 15 259 216 420 3.06 15 260 >300 439 3.56 15261 129.4 413 3.2 15 262 199.2 454 3.43 15 263 174.4 464 2.93 15 264157.6 412 2.45 15 265 175.5 478 3.55 15 266 >300 413 3.5 15 267 197.1446 2.93 15 268 143.1 445 3.16 15 269 182.7 452 3.32 15 270 275.1 4122.5 15 271 175.51 405 3.13 15 272 169.7 430 2.55 15 273 155.7 444 3.1815 274 151 433 3.49 15 275 157.7 477 3.72 15 276 143.2 416 2.36 15 277162 463 3.54 15 278 186.2 451 3.55 15 279 126 481 3.32 15 280 161 4683.16 15 281 179.4 399 3.06 15 282 180.4 418 2.94 15 283 185.1 443 3.3 15284 147.6 447 2.89 15 285 153.3 411 2.71 15 286 190.7 383 1.45 15 287n.d. 449 3.76 15 288 175 382 1.88 15 289 295.7 429 3.1 15 290 174.6 3793.2 15 291 144.6 441 3.18 15 292 176.6 398 2.31 15 293 n.d. 413 3.7 12294 150.4 411 2.99 15 295 182.1 417 2.64 15 296 174.4 464 2.93 15 297n.d. 401 3.48 12 298 144.6 415 3.46 15 299 132.1 440 2.95 15 300 199 4173.14 15 301 n.d. 464 3.19 15 302 n.d. 430 2.8 15 303 189.2 415 3.32 15304 165 518 3.51 15 305 n.d. 502 3.32 15 306 n.d. 427 3.65 15 307 154.5399 0.87 19 308 229.2 416 1.83 12 309 177.2 439 3.36 12 310 255.1 4233.38 12 311 119.9 441 3.24 15 312 122.8 441 3.18 15 313 150.9 433 2.8915 314 261.3 383 1.98 15 315 n.d. 467 3.28 15 316 166.8 361 2.77 15 317126.4 398 2.71 15 318 154.4 397 3.02 15 319 138.4 389 3.15 15 320 185.3426 2.85 15 321 172.4 425 3.3 15 322 152.9 403 3.4 15 323 145.9 440 3.0915 324 152.2 439 3.52 15 325 133.7 417 3.66 15 326 145.8 454 3.36 15 327147.1 453 3.77 15 328 n.d. 417 4.38 7 329 142 454 4.15 7 330 131 4534.46 7 331 n.d. 417 1.9 15 332 n.d. 463 3.53 15 333 256.4 414 2.6 15334 >300 387 3.22 15 335 >300 359 3.14 15 336 155.6 407 3.15 15 337209.5 401 3.45 15 338 146 415 3.7 15 339 n.d. 455 3.54 15 340 162.9 4563.09 15 341 n.d. 491 3.88 15 342 161.9 452 3.17 15 343 >300 419 3.41 15344 139.8 435 4.32 2 345 138.6 415 4.49 2 346 150.2 421 3.19 15 347 n.d.435 4.36 2 348 n.d. 379 3.56 15 349 n.d. 437 4.14 2 350 123.8 417 3.4315 351 >300 452 3.27 15 352 210.8 452 3.19 15 353 156.3 452 3.15 15 354205.5 480 3.71 15 355 n.d. 468 4.39 1 356 n.d. 468 4.39 1 357 151.2 4504.07 7 359 130 453 2.92 15 360 140.8 435 2.62 15 361 131.8 451 3.04 15362 126 481 3.32 15 363 183.5 419 4.19 8 364 172.4 401 2.2 15 365 142.6466 3.36 15 366 161.6 468 4.31 7 367 177.6 466 4.25 7 368 182.1 417 2.6415

Nuclear Magnetic Resonance (NMR)

For a number of compounds, ¹H NMR spectra were recorded either on aBruker 360, on a Bruker DPX-400 or on a Bruker AV-500 spectrometer withstandard pulse sequences, operating at 360 MHz, 400 MHz and 500 MHz,respectively. Chemical shifts (8) are reported in parts per million(ppm) downfield from tetramethylsilane (TMS), which was used as internalstandard.

Co. No. 1: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.30-0.40 (m, 2H), 0.59-0.67(m, 2H), 1.15-1.25 (m, 1H), 1.79 (qd, J=12.1, 3.5 Hz, 2H), 1.86 (br d,J=10.7 Hz, 2H), 2.29 (td, J=11.6, 2.3 Hz, 2H), 2.55 (tt, J=11.8, 3.9 Hz,1H), 2.97 (br d, J=11.3 Hz, 2H), 3.08 (d, J=6.6 Hz, 2H), 3.73 (s, 2H),7.18 (d, J=6.9 Hz, 1H), 7.19-7.22 (m, 1H), 7.22-7.28 (m, 2H), 7.28-7.34(m, 2H), 7.88 (d, J=7.2 Hz, 1H).

Co. No. 2: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.27-0.41 (m, 2H), 0.57-0.70(m, 2H), 1.11-1.22 (m, 1H), 2.08-2.19 (m, 2H), 2.20-2.31 (m, 1H), 2.36(td, J=13.2, 5.1 Hz, 1H), 3.06 (d, J=6.5 Hz, 2H), 3.33-3.43 (m, 2H),3.43-3.55 (m, 2H), 6.83 (d, J=7.6 Hz, 1H), 7.31-7.37 (m, 1H), 7.38-7.48(m, 4H), 7.98 (d, J=7.6 Hz, 1H).

Co. No. 3: ¹H NMR (360 MHz, CDCl₃) δ ppm 2.11-2.22 (m, 2H), 2.30 (td,J=13.2, 4.8 Hz, 1H), 2.41 (td, J=13.3, 4.9 Hz, 1H), 3.39 (td, J=12.2,2.0 Hz, 2H), 3.53-3.64 (m, 2H), 4.04 (q, J=9.9 Hz, 2H), 6.90 (d, J=7.3Hz, 1H), 7.31-7.38 (m, 1H), 7.38-7.50 (m, 4H), 7.91 (d, J=7.7 Hz, 1H).

Co. No. 4: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.97 (t, J=7.3 Hz, 3H),1.42-1.53 (m, 2H), 1.78-1.87 (m, 2H), 1.87-2.02 (m, 4H), 2.65-2.78 (m,1H), 2.99-3.08 (m, 2H), 3.12-3.24 (m, 2H), 3.61 (br d, J=12.5 Hz, 2H),6.76 (d, J=7.6 Hz, 1H), 7.20-7.30 (m, 3H), 7.30-7.39 (m, 2H), 7.81 (d,J=7.9 Hz, 1H).

Co. No. 5: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.20 (t, J=7.1 Hz, 3H),1.93-2.07 (m, 4H), 2.65-2.79 (m, 1H), 2.96-3.10 (m, 2H), 3.54 (q, J=6.9Hz, 2H), 3.75 (br d, J=12.5 Hz, 2H), 5.02 (s, 2H), 6.78 (d, J=7.6 Hz,1H), 7.21-7.31 (m, 3H), 7.32-7.38 (m, 2H), 8.10 (d, J=7.4 Hz, 1H).

Co. No. 6: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.31-0.36 (m, 2H), 0.58-0.66(m, 2H), 1.14-1.21 (m, 1H), 1.90 (br d, J=12.1 Hz, 2H), 2.20 (td,J=13.0, 4.6 Hz, 2 H), 3.06 (d, J=6.6 Hz, 2H), 3.33 (td, J=12.1, 2.0 Hz,2H), 3.48-3.57 (m, 2H), 5.13 (s, 2H), 6.81 (d, J=7.5 Hz, 1H), 7.20-7.28(m, 2H), 7.29-7.36 (m, 2H), 7.86 (d, J=7.5 Hz, 1H).

Co. No. 7: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.27-0.37 (m, 2H), 0.56-0.66(m, 2H), 1.12-1.21 (m, 1H), 1.72 (s, 6H), 1.91 (br d, J=11.3 Hz, 2H),2.01 (s, 1H), 2.00-2.10 (m, 2H), 2.98-3.08 (m, 2H), 3.04 (d, J=6.94 Hz,2H), 3.70 (br d, J=11.6 Hz, 2H), 3.80-3.91 (m, 1H), 6.78 (d, J=7.5 Hz,1H), 7.14-7.20 (m, 1H), 7.26-7.32 (m, 1H), 7.42 (dd, J=7.9, 1.0 Hz, 1H),7.46 (dd, J=7.8, 0.9 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H).

Co. No. 8: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.91 (br d, J=12.3 Hz, 2H),2.20 (td, J=13.0, 4.7 Hz, 2H), 3.38 (td, J=12.1, 1.8 Hz, 2H), 3.51-3.65(m, 2H), 4.03 (q, J=9.7 Hz, 2H), 5.14 (s, 2H), 6.89 (d, J=7.4 Hz, 1H),7.18-7.27 (m, 2H), 7.29-7.37 (m, 2H), 7.88 (d, J=7.6 Hz, 1H).

Co. No. 9: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.00 (d, J=6.5 Hz, 6H),1.73-1.88 (m, 2H), 1.96 (br d, J=10.6 Hz, 2H), 2.09-2.21 (m, 1H), 2.87(tt, J=12.1, 3.5 Hz, 1H), 3.01 (d, J=7.2 Hz, 2H), 3.22-3.32 (m, 2H),4.04 (br d, J=12.5 Hz, 2H), 7.19-7.26 (m, 1H), 7.27-7.39 (m, 5H), 8.68(d, J=7.6 Hz, 1H).

Co. No. 10: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.31 (t, J=7.5 Hz, 3H), 1.77(qd, J=12.6, 3.8 Hz, 2H), 1.95 (br d, J=11.3 Hz, 2H), 2.86-2.95 (m, 1H),3.00 (q, J=7.5 Hz, 2H), 3.34-3.42 (m, 2H), 4.32 (br d, J=13.3 Hz, 2H),6.96 (d, J=7.8 Hz, 1H), 7.19-7.25 (m, 1H), 7.26-7.37 (m, 4H), 8.34 (d,J=8.1 Hz, 1H).

Co. No. 11: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.84-1.99 (m, 2H), 2.08 (dd,J=12.4, 1.4 Hz, 2H), 2.42-2.57 (m, 4H), 2.86 (tt, J=12.1, 3.6 Hz, 2H),3.40 (td, J=12.8, 1.9 Hz, 2H), 3.63-3.72 (m, 4H), 4.01 (s, 2H), 4.33 (brd, J=13.3 Hz, 2H), 6.60 (d, J=8.1 Hz, 1H), 7.22-7.27 (m, 3H), 7.30-7.37(m, 2H), 8.28 (d, J=7.8 Hz, 1H).

Co. No. 12: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.52-1.67 (m, 2H), 1.69-1.86(m, 4H), 1.96 (br d, J=10.9 Hz, 2H), 2.10-2.23 (m, 2H), 2.85-2.98 (m,3H), 3.33-3.46 (m, 3H), 3.99 (s, 2H), 4.34 (br d, J=13.4 Hz, 2H), 7.02(d, J=7.9 Hz, 1H), 7.15-7.20 (m, 2H), 7.20-7.25 (m, 2H), 7.25-7.37 (m,6H), 8.45 (d, J=7.9 Hz, 1H).

Co. No. 13: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.27-0.37 (m, 2H), 0.56-0.69(m, 2H), 1.08-1.18 (m, 1H), 1.85-1.98 (m, 2H), 2.07 (br d, J=11.6 Hz,2H), 2.85 (tt, J=12.1, 3.5 Hz, 1H), 3.00 (d, J=6.6 Hz, 2H), 3.39 (td,J=12.8, 1.9 Hz, 2H), 4.31 (br d, J=13.3 Hz, 2H), 6.61 (d, J=7.8 Hz, 1H),7.22-7.27 (m, 3H), 7.30-7.38 (m, 2H), 7.85 (d, J=7.8 Hz, 1H).

Co. No. 14: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.84-1.96 (m, 2H), 2.06 (dd,J=13.1, 1.3 Hz, 2H), 2.08-2.14 (m, 1H), 2.14-2.26 (m, 1H), 2.46-2.56 (m,2H), 2.57-2.68 (m, 2H), 2.84 (tt, J=12.1, 3.6 Hz, 1H), 3.38 (td, J=12.8,1.9 Hz, 2H), 3.72-3.82 (m, 1H), 4.30 (br d, J=13.3 Hz, 2H), 6.58 (d,J=7.8 Hz, 1H), 7.21-7.27 (m, 3 H), 7.30-7.37 (m, 2H), 7.67 (d, J=7.8 Hz,1H).

Co. No. 15: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.24-0.34 (m, 2H), 0.53-0.64(m, 2H), 1.07-1.19 (m, 1H), 2.38-2.48 (m, 2H), 2.64 (d, J=12.7 Hz, 2H),2.91 (t, J=11.8 Hz, 2H), 3.02 (d, J=6.6 Hz, 2H), 3.51 (br. d, J=12.1 Hz,2H), 6.57 (d, J=7.5 Hz, 1H), 7.36-7.42 (m, 1H), 7.46 (t, J=7.7 Hz, 2H),7.49-7.53 (m, 2H), 7.76 (d, J=7.2 Hz, 1H).

Co. No. 16: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.93 (br d, J=13.4 Hz, 2H),2.14-2.26 (m, 2H), 3.02 (td, J=12.1, 2.3 Hz, 2H), 3.61-3.70 (m, 2H),4.04 (q, J=9.9 Hz, 2H), 4.48 (s, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.85 (d,J=7.4 Hz, 1H), 6.94 (td, J=7.4, 0.9 Hz, 1H), 7.19 (td, J=7.7, 1.3 Hz,1H), 7.24 (dd, J=7.4, 0.9 Hz, 1H), 7.91 (d, J=7.4 Hz, 1H).

Co. No. 17: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.27-0.40 (m, 2H), 0.56-0.69(m, 2H), 1.09-1.22 (m, 1H), 1.89 (br d, J=13.6 Hz, 2H), 2.14 (td,J=12.5, 3.7 Hz, 2H), 3.06 (d, J=6.7 Hz, 2H), 3.12 (br t, J=12.4 Hz, 2H),3.51 (br d, J=12.9 Hz, 2 H), 4.47 (s, 2H), 6.77 (d, J=7.6 Hz, 1H), 6.84(d, J=7.9 Hz, 1H), 6.93 (td, J=7.5, 0.8 Hz, 1H), 7.15-7.23 (m, 1H), 7.20(d, J=7.4 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H).

Co. No. 18: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.19 (d, J=6.0 Hz, 6H),2.08-2.19 (m, 2H), 2.20-2.31 (m, 1H), 2.36 (td, J=13.2, 5.1 Hz, 1H),3.39-3.46 (m, 2H), 3.46-3.57 (m, 2H), 3.70 (spt, J=6.1 Hz, 1H), 5.03 (s,2H), 6.84 (d, J=7.6 Hz, 1H), 7.32-7.37 (m, 1H), 7.39-7.47 (m, 4H), 8.26(d, J=7.9 Hz, 1H).

Co. No. 43: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.28-0.39 (m, 2H), 0.57-0.72(m, 2H), 1.06-1.22 (m, 1H), 1.78-2.11 (m, 4H), 2.72 (tt, J=11.5, 4.4 Hz,1H), 3.04 (d, J=6.6 Hz, 2H), 3.18 (td, J=12.1, 2.0 Hz, 2H), 3.62 (br. d,J=12.4 Hz, 2H), 6.76 (d, J=7.5 Hz, 1H), 7.21-7.28 (m, 3H), 7.34 (t,J=7.7 Hz, 2H), 7.92 (d, J=7.8 Hz, 1H).

Co. No. 297: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.25-0.45 (m, 2H),0.45-0.70 (m, 2H), 1.11-1.31 (m, 1H), 1.76 (qd, J=12.5, 3.2 Hz, 2H),1.93 (br. d, J=11.1 Hz, 2H), 2.91 (tt, J=11.8, 3.2 Hz, 1H), 3.06 (d,J=6.7 Hz, 2H), 3.46 (br. t, J=12.4 Hz, 2H), 3.57 (br. s., 1H), 3.89 (br.d, J=12.7 Hz, 2H), 7.18-7.24 (m, 1H), 7.24-7.29 (m, 2H), 7.29-7.36 (m,2H), 7.42 (d, J=7.9 Hz, 1H), 8.66 (d, J=8.1 Hz, 1H).

Co. No. 100: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (s, 6H), 3.18 (s, 2H),3.22-3.30 (m, 2H), 3.30-3.40 (m, 2H), 4.47 (q, J=10.8 Hz, 2H), 7.06-7.24(m, 4 H), 7.30 (d, J=7.4 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 8.57 (d, J=7.4Hz, 1H).

Co. No. 112: ¹H NMR (360 MHz, DMSO-d₆) δ ppm 0.14-0.40 (m, 2H),0.40-0.66 (m, 2H), 1.08-1.30 (m, 1H), 1.48 (s, 6H), 1.67 (br. d, J=12.4Hz, 2H), 2.10 (td, J=12.3, 5.5 Hz, 2H), 3.01 (d, J=6.6 Hz, 2H),3.39-3.54 (m, 4H), 7.05 (d, J=8.1 Hz, 1H), 7.18-7.44 (m, 4H), 8.48 (d,J=7.7 Hz, 1H).

Co. No. 119: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.26-0.40 (m, 2H), 0.51-0.70(m, 2H), 1.10-1.20 (m, 1H), 1.93 (br. d, J=13.4 Hz, 2H), 2.05-2.23 (m,2H), 3.06 (d, J=6.7 Hz, 2H), 3.11 (t, J=11.3 Hz, 2H), 3.48 (br. d,J=12.9 Hz, 2H), 4.50 (s, 2H), 6.78 (d, J=7.6 Hz, 1H), 6.88 (dd, J=7.2,5.1 Hz, 1H), 7.52 (dd, J=7.2, 1.4 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 8.08(dd, J=5.1, 1.4 Hz, 1H).

Co. No. 121: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.24-0.38 (m, 2H), 0.52-0.68(m, 2H), 0.95 (s, 4H), 1.05-1.21 (m, 1H), 3.03 (d, J=6.6 Hz, 2H), 3.20(t, J=4.6 Hz, 2H), 3.23 (br. s., 2H), 3.86 (t, J=4.6 Hz, 2H), 6.69 (d,J=7.5 Hz, 1H), 6.83 (t, J=7.2 Hz, 1H), 7.05 (d, J=7.8 Hz, 2H), 7.20-7.33(m, 2H), 7.91 (d, J=7.8 Hz, 1H).

Co. No. 123: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.03-0.15 (m, 2H), 0.42-0.52(m, 2H), 0.67-0.86 (m, 1H), 1.77 (q, J=7.2 Hz, 2H), 1.92 (qd, J=12.7,3.8 Hz, 2 H), 1.94-2.01 (m, 2H), 2.72 (tt, J=11.6, 4.0 Hz, 1H), 3.14 (t,J=7.5 Hz, 2H), 3.18 (ddd, J=12.1, 11.6, 2.0 Hz, 2H), 3.61 (br. d, J=12.7Hz, 2H), 6.76 (d, J=7.8 Hz, 1H), 7.21-7.27 (m, 3H), 7.31-7.38 (m, 2H),7.86 (d, J=7.8 Hz, 1H).

Co. No. 139: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.55 (s, 6H), 1.72-1.95 (m,2H), 2.22 (td, J=12.9, 4.7 Hz, 2H), 3.44 (td, J=12.4, 2.4 Hz, 2H),3.52-3.61 (m, 2H), 4.02 (q, J=9.7 Hz, 2H), 6.90 (d, J=7.4 Hz, 1H),7.10-7.22 (m, 2H), 7.29-7.36 (m, 2 H), 7.87 (d, J=7.6 Hz, 1H).

Co. No. 145: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.26-0.43 (m, 2H), 0.49-0.66(m, 2H), 1.12-1.24 (m, 1H), 1.86-2.09 (m, 4H), 2.60 (s, 3H), 2.61-2.73(m, 1 H), 2.86-2.99 (m, 2H), 3.05 (d, J=6.5 Hz, 2H), 3.23-3.40 (m, 2H),6.79 (d, J=7.6 Hz, 1H), 7.21-7.27 (m, 1H), 7.27-7.32 (m, 2H), 7.32-7.39(m, 2H), 7.81 (d, J=7.2 Hz, 1H).

Co. No. 147: ¹H NMR (360 MHz, DMSO-d₆) δ ppm 0.14-0.40 (m, 2H),0.41-0.66 (m, 2H), 1.01-1.31 (m, 1H), 1.78 (br. d, J=13.2 Hz, 2H), 2.34(td, J=13.5, 5.1 Hz, 2H), 3.03 (d, J=7.0 Hz, 2H), 3.44 (br. t, J=12.4Hz, 2H), 3.48-3.58 (m, 2H), 7.10 (d, J=7.7 Hz, 1H), 7.55-7.64 (m, 1H),7.64-7.71 (m, 2H), 7.71-7.78 (m, 1H), 8.55 (d, J=7.7 Hz, 1H).

Co. No. 148: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.23-0.37 (m, 2H), 0.53-0.66(m, 2H), 1.05-1.18 (m, 1H), 1.63 (s, 3H), 1.91 (ddd, J=13.2, 9.3, 3.5Hz, 2H), 2.41-2.55 (m, 2H), 3.01 (d, J=6.6 Hz, 2H), 3.21 (ddd, J=12.1,9.2, 2.9 Hz, 2H), 3.33-3.45 (m, 2H), 6.69 (d, J=7.8 Hz, 1H), 7.15 (ddd,J=7.5, 4.9, 0.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.68 (td, J=7.7, 1.9Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.60 (dd, J=4.6, 0.9 Hz, 1H).

Co. No. 153: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.89 (qd, J=12.7, 3.2 Hz,2H), 1.92-2.01 (m, 2H), 2.70 (tt, J=11.6, 4.0 Hz, 1H), 3.16 (br. t,J=11.1 Hz, 2H), 3.60 (br. d, J=12.7 Hz, 2H), 4.65 (s, 2H), 6.69 (d,J=7.8 Hz, 1H), 7.18 (dd, J=6.9, 5.2 Hz, 1H), 7.21-7.27 (m, 3H),7.30-7.35 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.63 (td, J=7.7, 1.7 Hz, 1H),8.33 (d, J=7.8 Hz, 1H), 8.51 (d, J=4.3 Hz, 1H).

Co. No. 171: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.24-0.44 (m, 2H), 0.50-0.68(m, 2H), 1.10-1.30 (m, 1H), 1.43 (t, J=7.5 Hz, 3H), 1.84-2.08 (m, 4H),2.57-2.73 (m, 1H), 2.83-2.99 (m, 2H), 3.04 (br. d, J=6.7 Hz, 2H), 3.13(q, J=7.5 Hz, 2H), 3.21 (d, J=12.0 Hz, 2H), 6.81 (d, J=7.4 Hz, 1H),7.20-7.28 (m, 1H), 7.28-7.32 (m, 2H), 7.32-7.40 (m, 2H), 7.81 (d, J=7.4Hz, 1H).

Co. No. 159: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.22-0.38 (m, 2H), 0.52-0.66(m, 2H), 1.03-1.10 (m, 2H), 1.14-1.24 (m, 1H), 1.66-1.80 (m, 2H),1.90-2.04 (m, 4H), 2.34 (tt, J=8.7, 5.5 Hz, 1H), 2.59-2.75 (m, 1H),2.90-2.97 (m, 2H), 2.99 (d, J=6.6 Hz, 2H), 3.52 (br. d, J=11.8 Hz, 2H),6.76 (d, J=7.5 Hz, 1H), 7.24 (t, J=7.2 Hz, 1H), 7.27-7.31 (m, 2H),7.31-7.38 (m, 2H), 7.72 (d, J=7.2 Hz, 1H).

Co. No. 182: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.26-0.45 (m, 2H), 0.54-0.71(m, 2H), 1.07-1.20 (m, 1H), 1.22 (d, J=6.5 Hz, 3H), 3.06 (d, J=6.7 Hz,2H), 3.15-3.29 (m, 2H), 3.30-3.41 (m, 2H), 3.47 (dd, J=11.3, 3.0 Hz,1H), 3.49-3.58 (m, 1H), 3.97-4.08 (m, 1H), 6.29 (tt, J=8.8, 2.2 Hz, 1H),6.32-6.44 (m, 2H), 6.78 (d, J=7.6 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H).

Co. No. 200: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.27-0.39 (m, 2H), 0.55-0.67(m, 2H), 1.09-1.19 (m, 1H), 1.52 (s, 6H), 1.77 (d, J=12.4 Hz, 2H), 2.12(td, J=12.9, 4.5 Hz, 2H), 3.05 (d, J=6.9 Hz, 2H), 3.39 (br. d, J=12.1Hz, 2H), 3.54 (t, J=12.0 Hz, 2H), 6.81 (dd, J=8.4, 2.0 Hz, 1H), 6.82 (d,J=7.2 Hz, 1H), 7.00 (td, J=8.5, 2.3 Hz, 1H), 7.09 (dd, J=8.2, 4.8 Hz,1H), 7.94 (d, J=7.8 Hz, 1H).

Co. No. 204: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.25-0.40 (m, 2H), 0.47-0.66(m, 2H), 1.15-1.25 (m, 1H), 1.84 (br d, J=12.4 Hz, 2H), 2.01 (qd,J=12.5, 3.8 Hz, 2H), 2.68 (s, 3H), 2.84 (br t, J=11.1 Hz, 2H), 3.04 (tt,J=12.1, 3.8 Hz, 1H), 3.06 (d, J=6.6 Hz, 2H), 3.50 (br d, J=11.6 Hz, 2H),6.79-6.88 (m, 2H), 6.85 (d, J=7.2 Hz, 1H), 6.93-7.03 (m, 1H), 7.84 (d,J=7.2 Hz, 1H).

Co. No. 206: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.86-2.04 (m, 2H), 2.05-2.15(m, 2H), 2.87 (tt, J=12.1, 3.8 Hz, 1H), 3.40 (td, J=12.7, 2.3 Hz, 2H),4.26-4.41 (m, 2H), 6.72 (d, J=7.9 Hz, 1H), 7.22-7.28 (m, 3H), 7.30-7.39(m, 2H), 8.10-8.17 (m, 2H), 8.38 (d, J=7.6 Hz, 1H), 8.72-8.79 (m, 2H).

Co. No. 207: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.23-0.39 (m, 2H), 0.47-0.67(m, 2H), 1.11-1.22 (m, 1H), 1.92-2.11 (m, 4H), 2.64-2.77 (m, 1H), 2.99(td, J=11.3, 3.5 Hz, 2H), 3.06 (d, J=6.6 Hz, 2H), 3.69 (br. d, J=11.8Hz, 2H), 6.75 (d, J=7.2 Hz, 1H), 7.22-7.27 (m, 1H), 7.28-7.32 (m, 2H),7.32-7.39 (m, 2H), 7.89 (d, J=7.2 Hz, 1H).

Co. No. 224: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.27-0.41 (m, 2H), 0.56-0.70(m, 2H), 1.14-1.24 (m, 1H), 2.69 (br. t, J=4.6 Hz, 4H), 3.07 (br. t,J=4.0 Hz, 4 H), 3.10 (d, J=6.9 Hz, 2H), 3.81 (d, J=1.2 Hz, 2H),6.72-6.85 (m, 2H), 6.86-6.95 (m, 1H), 7.40 (d, J=7.2 Hz, 1H), 8.06 (d,J=7.2 Hz, 1H).

Co. No. 244: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.25-0.41 (m, 2H), 0.58-0.71(m, 2H), 1.15-1.24 (m, 1H), 1.36 (d, J=6.4 Hz, 3H), 1.54-1.67 (m, 1H),1.68-1.76 (m, 1H), 1.77-1.89 (m, 1H), 1.90-2.02 (m, 1H), 2.07 (br t,J=11.1 Hz, 1H), 2.18 (td, J=11.4, 2.3 Hz, 1H), 2.54 (tt, J=12.1, 3.8 Hz,1H), 2.59-2.69 (m, 1H), 2.98-3.20 (m, 2H), 3.33-3.46 (m, 1H), 3.83-3.96(m, 1H), 7.17-7.22 (m, 1H), 7.22 (d, J=7.2 Hz, 2H), 7.31 (t, J=7.7 Hz,2H), 7.49 (d, J=7.2 Hz, 1H), 8.06 (d, J=7.5 Hz, 1H).

Co. No. 250: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.31-0.41 (m, 2H), 0.59-0.69(m, 2H), 1.14-1.24 (m, 1H), 2.02 (br t, J=11.7 Hz, 2H), 2.05-2.13 (m,1H), 2.17 (td, J=13.2, 4.8 Hz, 1H), 2.65 (br t, J=11.0 Hz, 2H),2.71-2.81 (m, 2H), 3.11 (d, J=6.9 Hz, 2H), 3.82 (d, J=1.4 Hz, 2H),7.29-7.34 (m, 1H), 7.36-7.46 (m, 4H), 7.39 (d, J=7.2 Hz, 1H), 8.06 (d,J=7.2 Hz, 1H).

Co. No. 282: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.27-0.41 (m, 2H), 0.56-0.69(m, 2H), 1.14-1.25 (m, 1H), 2.59-2.72 (m, 4H), 3.09 (d, J=6.6 Hz, 2H),3.24 (br. s., 4H), 3.77 (s, 2H), 6.75-6.89 (m, 2H), 6.88-6.99 (m, 1H),7.18 (d, J=7.2 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H).

Co. No. 298: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.27-0.40 (m, 1H),0.45-0.62 (m, 2H), 1.14-1.34 (m, 1H), 1.94 (br. d, J=13.3 Hz, 2H),2.15-2.34 (m, 2H), 2.81-2.95 (m, 1H), 3.12 (d, J=6.9 Hz, 2H), 3.16-3.33(m, 2H), 3.54 (br. d, J=11.6 Hz, 2H), 4.61 (br. s., 2H), 7.17-7.29 (m,3H), 7.34 (t, J=7.5 Hz, 2H), 7.88 (d, J=7.2 Hz, 1H), 8.93 (d, J=7.2 Hz,1H), 11.22 (br. s., 1H).

D. Pharmacological Examples

The compounds provided in the present invention are positive allostericmodulators of mGluR2. These compounds appear to potentiate glutamateresponses by binding to an allosteric site other than the glutamatebinding site. The response of mGluR2 to a concentration of glutamate isincreased when compounds of Formula (I) are present. Compounds ofFormula (I) are expected to have their effect substantially at mGluR2 byvirtue of their ability to enhance the function of the receptor. Thebehaviour of positive allosteric modulators tested at mGluR2 using the[³⁵S]GTPγS binding assay method described below and which is suitablefor the identification of such compounds, and more particularly thecompounds according to Formula (I), is shown in Table 3.

[³⁵S]GTPγS Binding Assay

The [³⁵S]GTPγS binding assay is a functional membrane-based assay usedto study G-protein coupled receptor (GPCR) function wherebyincorporation of a non-hydrolysable form of GTP, [³⁵S]GTPγS (guanosine5′-triphosphate, labelled with gamma-emitting ³⁵S), is measured. TheG-protein a subunit catalyzes the exchange of guanosine 5′-diphosphate(GDP) by guanosine triphosphate (GTP) and on activation of the GPCR byan agonist, [³⁵S]GTPγS, becomes incorporated and cannot be cleaved tocontinue the exchange cycle (Harper (1998) Current Protocols inPharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount ofradioactive [³⁵S]GTPγS incorporation is a direct measure of the activityof the G-protein and hence the activity of the agonist can bedetermined. mGluR2 receptors are shown to be preferentially coupled toGγi-protein, a preferential coupling for this method, and hence it iswidely used to study receptor activation of mGluR2 receptors both inrecombinant cell lines and in tissues. Here we describe the use of the[³⁵S]GTPγS binding assay using membranes from cells transfected with thehuman mGluR2 receptor and adapted from Schaffhauser et al. ((2003)Molecular Pharmacology 4:798-810) for the detection of the positiveallosteric modulation (PAM) properties of the compounds of thisinvention.

Membrane Preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mMbutyrate for 24 h, prior to washing in PBS, and then collected byscraping in homogenisation buffer (50 mM Tris-HCl buffer, pH 7.4, 4°C.). Cell lysates were homogenized briefly using an ultra-turraxhomogenizer. The homogenate was centrifuged at 16,000 RPM (Sorvall RC-5Cplus rotor SS-34) for 10 minutes and the supernatant discarded. Thepellet was resuspended in 5 mM Tris-HCl, pH 7.4 and centrifuged again(18,000 RPM, 20 min, 4° C.). The final pellet was resuspended in 50mMTris-HCl, pH 7.4 and stored at −80° C. in appropriate aliquots beforeuse. Protein concentration was determined by the Bradford method(Bio-Rad, USA) with bovine serum albumin as standard.

[³⁵S]GTPγS Binding Assay

Measurement of mGluR2 positive allosteric modulatory activity of testcompounds was performed as follows. Test compounds and glutamate werediluted in assay buffer containing 10 mM HEPES acid, 10 mM HEPES salt,pH 7.4, 100 mM NaCl, 3 mM MgCl₂ and 10 μM GDP. Human mGlu2receptor-containing membranes were thawed on ice and diluted in assaybuffer supplemented with 14 μg/ml saponin. Membranes were pre-incubatedwith compound alone or together with a predefined (˜EC₂₀) concentrationof glutamate (PAM assay) for 30 min at 30° C. After addition of[³⁵S]GTPγS (f.c. 0.1 nM) microplates were shaken briefly and furtherincubated to allow [³⁵S]GTPγS incorporation on activation (30 minutes,30° C.). Final assay mixtures contained 7 μg of membrane protein in 10mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl₂,10 μMGDP and 10 μg/ml saponin. Total reaction volume was 200 μl. Reactionswere terminated by rapid filtration through Unifilter-96 GF/B filterplates (Packard, Meriden, Conn.) using a 96-well Packard filtermateharvester. Filters were washed 6 times with ice-cold 10 mM NaH₂PO₄/10 mMNa₂HPO₄, pH 7.4. Filters were then air-dried, and 40 μl of liquidscintillation cocktail (Microscint-O) was added to each well.Membrane-bound radioactivity was counted in a Microplate Scintillationand Luminescence Counter from Packard.

Data Analysis

The concentration-response curves of representative compounds of thepresent invention-obtained in the presence of EC₂₀ of mGluR2 agonistglutamate to determine positive allosteric modulation (PAM)- weregenerated using the Lexis software interface (developed at J&J). Datawere calculated as % of the control glutamate response, defined as themaximal response that is generated upon addition of glutamate alone.Sigmoid concentration-response curves plotting these percentages versusthe log concentration of the test compound were analyzed usingnon-linear regression analysis. The concentration producing half-maximaleffect is then calculated as EC₅₀.

The pEC₅₀ values below were calculated as the −log EC₅₀, when the EC₅₀is expressed in M. Table 3 below shows the pharmacological data obtainedfor a selected set of compounds.

Motor Activity (Video Tracking) Apparatus and General Procedure

On the day of experiments, the mice were brought into the proceduralroom. They were housed individually and allowed to acclimate for atleast a half hour prior to testing. Although the studies were conductedduring the light cycle (from 8:00 to 16:00 h), the procedure room wasonly sparsely lit (3 to 30 LUX) to provide better contrast for the videotracking. Local lighting was used for the injection procedures. Duringeach trial, an individual mouse was placed in an open field arena (greyPVC cylinder with a height of 40 cm and a diameter of 22.5 cm). Eacharena was placed on an infrared LED (8×8 LEDs)-lit box (white PVCsquared box; 40×40 cm²; height 12.5 cm). Each mouse was placed in thecenter of the arena and allowed to explore freely for 30 min. After eachtrial, the arena was cleaned with a wet and subsequently with a drycleaning cloth. An infrared sensitive tube camera and a white lightsource (in arena: 4-7 LUX) were mounted to the ceiling above theobservation chamber to record and input activity to a computer. Animalbehavior was recorded and analyzed using the Noldus Ethovision XT VideoTracking System (Version 3.1; Noldus, Wageningen, The Netherlands). Thetotal distance traveled (cm) was calculated. Data were then exported todata management systems for further analysis and reporting.

Phencyclidine (PCP)-Induced Hyperlocomotion in Mice

Test compound or solvent was administered at a pre-defined time beforemeasurement (standard: 30 min) to male NMRI mice that were challengedwith phencyclidine (PCP; 5 mg/kg, s.c.) 30 min before measurement.Activity was measured for a period of 30 min. Criterion for drug-inducedinhibition of hyperlocomotion: total distance<5500 counts (3.9% falsepositives in controls; n=154). The results are shown in table 4a below.

d-Amphetamine-Induced Hyperlocomotion in Mice

Test compound or solvent was administered at a pre-defined time beforemeasurement (standard: 30 min) to male NMRI mice that were challengedwith d-amphetamine (5 mg/kg, s.c.) 30 min before measurement. Activitywas measured for a period of 30 min. Criterion for drug-inducedinhibition of hyperlocomotion: total distance<5500 counts (4.1% falsepositives in controls; n=410). Compound 43 inhibited theamphetamine-induced hyperlocomotion (ED₅₀: 37 mg/kg s.c.).

Conditioned Avoidance Response (CAR) Test Apparatus

The apparatus consisted of an inner box surrounded by an outer box. Theinner box was composed of four walls of transparent, synthetic material(length×width×height: 30×30×30 cm), an open top, and a grid floor madeof 15 pairs of iron bars (2 mm diameter; 6 mm inter-bar distance). Oddand even bars were connected with a source of alternative current (1.0mA; Coulbourn Instruments Solid State Shocker/Distributor), which couldbe interrupted by a switch. The outer box was composed of the samematerial (length×width×height: 40×40×36 cm), also with an open top, witha distance of 5 cm between the inner and outer box on all sides. Todecrease the amount of environmental stimuli, three walls of the outerbox were made non-transparent. The front wall was left transparent toallow the necessary inspection of the animal during the test. The upperedge of the outer and inner box served as a target for the rats on whichto jump with fore- and hind-paws, respectively.

Avoidance Conditioning and Selection of Animals

From their arrival in the laboratory on the experimental day, male WigaWistar rats (230±30 g) were housed in individual cages provided withbedding material. The rats received 5 training sessions at 15-min timeintervals over a 1-h period during which, the rats were conditioned toavoid an electric shock: the rat was placed on the non-electrified gridfloor and the grid was electrified 10 s later for not more than 30 s, ifthe rat did not jump out of the box. Only rats that showed correctavoidance responses in all the last 3 training sessions were includedfor further experiments, and received the test compound or solventimmediately after the last training session.

Experimental Sessions

The rats were tested 3 times, i.e. at 60, 90 and 120 min after theinjection of test compound or solvent. Latency to avoidance wasrecorded. The median avoidance response obtained over the threeexperimental sessions for each rat were used for further calculations. Amedian avoidance latency>8 s was selected as an all-or-none criterionfor drug-induced inhibition of avoidance (occurring in only 1.5% ofsolvent-pretreated control rats; n=66). The results of this test areshown in table 4b below.

Reversal of Memantine-Induced Brain Activation in Mice

NMDA receptor hypofunction is hypothesized to be involved inschizophrenia. Subanaesthetic doses of the NMDA antagonist ketamine havebeen shown to induce behavioural, perceptual and cognitive changes inhealthy volunteers similar to positive, negative and cognitive symptomsof schizophrenia.

Autoradiographic assessment of radiolabeled [¹⁴C]-2-deoxyglucose([¹⁴C]2DG) uptake is commonly used to investigate brain activation. Inhumans, cerebral blood flow is increased in specific brain regions afteradministration of a subanaesthetic dose of ketamine. Ketamine-inducedalterations in 2DG uptake have therefore been suggested as a model toinvestigate the effects of antipsychotic drugs. When evaluatingdifferent NMDA antagonists, we found that memantine induced more robustbrain activation with a greater dynamic window for testing drugs.Validating our choice to use memantine, we found that in accordance tothe ketamine model, the atypical antipsychotic clozapine reversedmemantine induced brain glucose metabolism, whereas the typicalantipsychotic haloperidol was inactive in this test. In the same model,we have found that the mGlu2/3 agonist LY404039 inhibitedmemantine-induced increase in 2DG uptake in mouse brain.

Method

Male mice (C57BL/6, weight 24-28 g, fasted overnight; n=10 animals pergroup) were treated with vehicle or test compound (s.c.) in randomizedorder (t=0 min). Memantine (20 mg/kg, s.c.) was injected 30 min later(t=30 min). At t=45 min, [¹⁴C]2DG (0.16 μCi/g) was administeredintraperitoneally (i.p.), followed by a 45 min uptake period. Animalswere decapitated (t=90 min), plasma glucose levels measured, the brainremoved, rapidly frozen and stored at −20° C. until sectioned. Brainsections were exposed together to a precalibrated [¹⁴C]standard on film,which was developed after four days of exposure. Local tissue[¹⁴C]concentration (nCi/mg tissue equivalent—TEQ-) in each region ofinterest was determined.

Data was analyzed statistically using a two-way ANOVA analysis followedby post-hoc tests (memantine response versus reversal by the compound).The results are shown in table 5 below, expressed as lowest active dose(L.A.D.) required to exert a statistically significant (p<0.05)reduction of 2DG uptake in the hippocampus compared to memantineresponse.

Sleep Wake Electroencephalography (SW-EEG) in Rats

SW-EEG analyses are a highly sensitive read-out of a compound's centralfunctional activity that may provide additional insight in the potentialtherapeutic application (i.e. via drug classification fingerprinting).Systemic administration of an mGlu2/3 receptor agonist and PAM has beenshown to selectively suppress rapid eye movement (REM) sleep in rat.Internal efforts have confirmed that this effect is mGlu2receptor-mediated, i.e. is absent in mGlu2 KO mice. Sleep abnormalitiesare often associated with CNS disorders; as such, the potential use ofmGlu2 modulators could also have benefit in the treatment of CNSdisorders in which (REM) sleep aberrations are manifested. Morespecifically, the combination of a persistent reduction in REMoccurrence and an increase in REM latency is one of the key features ofthe typical SW architecture fingerprint of most clinically activeantidepressants.

We investigated the effects of oral administration of compoundsaccording to the invention on SW organization in rats. The mGlu2/3receptor agonists LY404039 and LY354740 were also evaluated to allowcomparison.

A selection of compounds was found to dose-dependently decrease REMsleep in rats (lowest active dose was 3 or 10 mg/kg, p.o.). Similarly,acute dosing of LY354740 showed a decrease in REM sleep (lowest activedose 3 mg/kg, s.c.); also compound LY404039 was found to affect REMsleep (3 mg/kg, p.o.) qualitatively in a comparable way.

Subchronic treatment (once daily dosing for 7 days) with LY354740 (1, 3,10 mg/kg, s.c.) led to tolerance (from day 3 onward, the effect on REMsleep started to diminish, with loss of activity of the 3 and 10 mg/kgdose), whereas a similar treatment schedule (3, 10 and 30 mg/kg, p.o.)did not diminish the effects of compound 43.

TABLE 3 Pharmacological data for compounds according to the invention.GTPγS-hR2 PAM Co. No. pEC₅₀ 1 6.68 2 7.41 3 6.94 4 7.62 5 6.88^(‡) 66.89^(‡) 7 7.4 8 7.01^(‡) 9 6.57 10 6.16 11 5.12^(‡) 12 7.33 13 7.13 146.37 15 6.75 16 6.75 17 7.45 18 7.16 19 n.c. 20 7.25 21 6.61 22 7.26 236.98 24 6.33^(‡) 25 6.42 26 6.99 27 7.51 28 6.53 29 n.c. 30 6.95 31 6.2732 7.03 33 5.15^(‡) 34 7.35 35 5.91 36 5.95^(‡) 37 6.51 38 7.74 39 7.5240 6.67 41 7.21 42 6.83 43 7.79 44 6.02 45 6.07^(‡) 46 8.03 47 n.c. 486.9^(‡) 49 n.c. 50 n.c. 51 8.35^(‡) 52 6.98^(‡) 53 6.07 54 6.95 55 8.2256 6.02^(‡) 57 8.16^(‡) 58 6.23 59 7.17 60 6.33 61 7.98 62 6.41 63 6.0864 6.65 65 8.41 66 6.94 67 7.36 68 7.55 69 n.t. 70 n.t. 71 6.65^(‡) 727.06 73 6.13 74 6.85 75 7.05 76 6.93 77 7.68^(‡) 78 6.83 79 7.28 80 7.2781 6.85 82 7.51 83 7.64 84 7.86 85 8.06 86 7.95 87 6.94 88 6.18 896.46^(‡) 90 6.61 91 7.27 92 6.87 93 6.53 94 n.c. 95 5.93^(‡) 96 5.88 976.3 98 6.75 99 6.03 100 6.51 101 6.24 102 6.5 103 5.63^(‡) 104 7.7 1056.17^(‡) 106 6.45 107 7.22 108 6.91^(‡) 109 7.29 110 6.86 111 6.26 1128.19 113 7.59 114 6.33 115 n.c. 116 n.c. 117 6.68 118 6.83 119 5.76 1206.31 121 6.63 122 7.3 123 7.39 124 6.98 125 n.c. 126 n.c. 127 6.42 1286.73 129 6.92 130 6.4 131 7.34 132 6.68 133 7.05 134 7.17 135 6.77 1367.69^(‡) 137 6.87 138 n.c. 139 8.36 140 6.55 141 6.95 142 6.55^(‡) 143n.c. 144 6.25 145 6.38 146 7.02 147 6.61 148 6.44 149 6.5^(‡) 1506.97^(‡) 151 7.48 152 6.78 153 6.71 154 7.13 155 6.83^(‡) 156 n.c. 1576.18 158 6.14 159 6.69 160 6.73 161 5.68^(‡) 162 6.93 163 6.97^(‡) 1646.46 165 6.41 166 7.22 167 6.47^(‡) 168 7.22 169 7.77^(‡) 170 5.84^(‡)171 6.6 172 n.c. 173 6.32^(‡) 174 5.91^(‡) 175 6.33 176 6.3 177 7.67 178n.c. 179 5.79^(‡) 180 7.23 181 n.c. 182 7.03 183 7.08 184 6.81 185 8.26186 7.27 187 6.19 188 8^(‡) 189 6.4 190 6.5 191 6.76 192 6.63 193 8.26194 7.69 195 7.98 196 7.06 197 7.82^(‡) 198 6.29^(‡) 199 6.8 200 8.45201 6.9 202 7.86^(‡) 203 6.73 204 5.87^(‡) 205 6.61^(‡) 206 n.c. 2077.45 208 7.06 209 7.52^(‡) 210 6.5 211 7.44 212 8.08 213 6.03^(‡) 2147.68 215 5.6^(‡) 216 6.68 217 n.t. 218 6.05^(‡) 219 7.24^(‡) 220 7.37221 7.55 222 n.c. 223 6.03^(‡) 224 7.06 225 6.8^(‡) 226 6.4 227 6.31^(‡)228 n.c. 229 n.c. 230 5.61^(‡) 231 n.c. 232 7.64 233 7.23 234 7.83^(‡)235 n.c. 236 n.t. 237 n.c. 238 6.08^(‡) 239 6.97 240 6.41^(‡) 2415.75^(‡) 242 5.86 243 7.91 244 7.62^(‡) 245 7.41 246 6.79 247 6.72 2487.55 249 7.48^(‡) 250 6.93 251 n.c. 252 n.c. 253 6.87 254 6.63 2556.78^(‡) 256 n.c. 257 6.74 258 6.11^(‡) 259 6.67^(‡) 260 7.47 2616.84^(‡) 262 7.27^(‡) 263 6.95 264 5.71^(‡) 265 7.56 266 7.88^(‡) 2676.41 268 7.59^(‡) 269 7.59 270 5.58^(‡) 271 7.24^(‡) 272 6.01 273 7.33274 7.83^(‡) 275 7.71 276 6.78^(‡) 277 7.72 278 8.01 279 7.24^(‡) 2805.95^(‡) 281 7.06 282 6.69^(‡) 283 7.26 284 6.5 285 6.77 286 n.c. 2877.87^(‡) 288 n.c. 289 6.87 290 7.13 291 6.83 292 5.84^(‡) 293 6.31^(‡)294 6.59 295 6.32^(‡) 296 6.95 297 7.61^(‡) 298 7.77 299 5.97^(‡) 3007.24 301 7.45^(‡) 302 6.55 303 7.3 304 6.12 305 n.t. 306 n.t. 307 6.37308 n.c. 309 n.c. 310 n.t. 311 7.05 312 6.82 313 6.44^(‡) 314 6.31^(‡)315 7.24 316 5.83^(‡) 317 n.c. 318 6.21 319 6.84 320 6.02 321 6.96 3227.29 323 6.61^(‡) 324 7.27 325 7.55 326 6.92 327 7.71^(‡) 328 n.t. 329n.t. 330 n.t. 331 n.c. 332 n.t. 333 6.33^(‡) 334 n.c. 335 6.42^(‡) 3366.08^(‡) 337 7.23^(‡) 338 7.42^(‡) 339 7.15^(‡) 340 6.57^(‡) 341 7.9^(‡)342 7.35^(‡) 343 n.c. 344 6.64^(‡) 345 7.39^(‡) 346 6.5^(‡) 347 n.t. 348n.t. 349 n.t. 350 7.11^(‡) 351 7.46^(‡) 352 7.71^(‡) 353 7.24^(‡) 3548.25^(‡) 355 n.t. 356 n.t. 357 n.t. 359 7^(‡) 360 6.44^(‡) 361 7.25^(‡)362 7.24^(‡) 363 5.96^(‡) 364 n.c. 365 6.77^(‡) 366 6.98^(‡) 3677.23^(‡) 368 6.32^(‡) n.t. means not tested n.c. means that the EC₅₀could not be calculated ^(‡)means tested once

EC₅₀ values were not calculated in cases where theconcentration-response curve did not reach a plateau level. Bydefinition, the EC₅₀ value of a compound is the concentration needed toreach 50% of the maximal response.

All compounds were tested in presence of mGluR2 agonist, glutamate at apredetermined EC₂₀ concentration, to determine positive allostericmodulation (GTPγS-PAM). pEC₅₀ values were calculated from aconcentration-response experiment of at least 10 concentrations. If moreexperiments were performed, the average pEC₅₀ value is reported anderror deviation was <0.5.

TABLE 4a Pharmacological data for compounds according to the inventionin the (PCP)-induced hyperlocomotion test in mice. Mice ED₅₀ (mg/kg) Co.No. PCP-Inh. 30     5^(a)) 3    15.2 43     5.4 44  >40 66    17.4 76    3.1 78 ≧10 17    15.2 15  >10 97     6.3^(a)) 98  >40 112     2.0151    12.6^(a)) 298     5.0^(a)) 221    12.6^(a)) 224     2.0^(a)) 226    7.9^(a)) 240    12.6^(a)) 244     5.0^(a)) 250  >10 307    1.25^(a)) 278     1.25^(a)) 281     3.2^(a)) 286    20^(a)) 288   12.6^(a)) 303    20^(a)) 300    12.6^(a)) 311     3.2^(a)) 319   20^(a)) 320     3.2^(a)) 323     1.25^(a)) 325     7.9^(a)) 322    7.9^(a)) 326     3.1^(a)) 316    12.6^(a)) 317     5.0^(a)) ED₅₀ isthe dose (mg/kg body weight) at which 50% of the tested animals show theeffect; Inh. means inhibition. ^(a))Estimated ED₅₀ values (n = 3 perdose; 4-fold separation between doses)

TABLE 4b Pharmacological data for compounds according to the inventionin the CAR test in rats. Rats ED₅₀ Co. (mg/kg) No. CAR-Inh. 3   14.1*^(a))    10.7 43    16.3*     2.35 76 ≧40* 15 ≧40* 97   32*^(b))    16^(b)) 298     5.0^(b)) 224     5.0^(b)) ED₅₀ is thedose (mg/kg body weight) at which 50% of the tested animals show theeffect. Inh. means inhibition; *means the compound was administeredorally. ^(a))Estimated ED₅₀ value (irregular dose-response)^(b))Estimated ED₅₀ values (n = 3 per dose; 4-fold separation betweendoses)

Compounds 30, 3, 43, 66, 76, 17, 97, 112, 151, 298, 221, 224, 226, 240,307, 278, 281, 286, 288, 298, 303, 300, 311, 319, 320, 323, 325, 326,316 and 317 inhibited PCP-induced hyperlocomotion in mice, compound 43was also active against d-amphetamine-induced hyperlocomotion in mice,and compounds 3, 43, 97, 224 and 298 also inhibited the conditionedavoidance response in rats, attesting to their possible antipsychoticpotential.

TABLE 5 Pharmacological data for compounds according to the invention inthe reversal of memantine-induced brain activation in mice. Mice L.A.D.Co. No. (mg/kg, s.c.) 3 ≦2.5 43 ≦2.5 97 ≦10 98 ≦10 112 ≦2.5 151 10≦means that the compound was active at the indicated dose level and wasnot tested at lower doses.

The observed reversal in memantine-induced 2DG uptake indicates thatmGlu2 PAMs may have antipsychotic-like properties.

E. Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound of formula (I)

or a stereochemically isomeric form thereof wherein n is selected fromthe group consisting of 0, 1 and 2; m is selected from the groupconsisting of 0, 1, and 2; R is selected from methyl or trifluoromethyl;R¹ is selected from the group consisting of hydrogen; C₁₋₆alkyl;(C₁₋₃alkyloxy)-C₁₋₃ alkyl; [(C₁₋₃ alkyloxy)C₁₋₃ alkyloxy]C₁₋₃ alkyl;C₁₋₃ alkyl substituted with one or more independently selected halosubstituents; unsubstituted phenyl; unsubstituted benzyl; benzylsubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halo, C₁₋₃ alkyl, C₁₋₃ alkyloxy, C₁₋₃ alkyloxyC₁₋₃alkyl, hydroxyC₁₋₃alkyl, cyano, hydroxyl, amino, C(═O)R′, C(═O)OR′,C(═O)NR′R″, mono- or di(C₁₋₃ alkyl)amino, morpholinyl,(C₃₋₇cycloalkyl)C₁₋₃ alkyloxy, trifluoromethyl and trifluoromethoxy,wherein R′ and R″ are independently selected from hydrogen andC₁₋₆alkyl; (benzyloxy)C₁₋₃ alkyl; unsubstituted C₃₋₇cycloalkyl;C₃₋₇cycloalkyl substituted with C₁₋₃alkyl substituted with one or moreindependently selected halo substituents; (C₃₋₇cycloalkyl)C₁₋₃ alkyl;[(C₃₋₇cycloalkyl)C₁₋₃alkyloxy]C₁₋₃alkyl; (C₃₋₇cycloalkyl)C₁₋₃alkyloxy;4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methyl; Het¹; Het¹C₁₋₃alkyl; Het²; and Het²C₁₋₃ alkyl; R² is selected from the groupconsisting of cyano; halo; C₁₋₃alkyl substituted with one or moreindependently selected halo substituents; C₁₋₃alkyloxy substituted withone or more independently selected halo substituents; C₁₋₃alkyl;C₃₋₇cycloalkyl; and (C₃₋₇cycloalkyl)C₁₋₃ alkyl;

is an N-containing heterocycle selected from the group consisting of(L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L-h) below

wherein R^(3a) is selected from the group consisting of C₁₋₃alkyl;C₁₋₃alkyl substituted with one or more independently selected halosubstituents; unsubstituted C₃₋₇cycloalkyl; C₃₋₇cycloalkyl substitutedwith 1 or 2 substituents independently selected from C₁₋₃alkyl,C₁₋₃alkyl substituted with one or more independently selected halosubstituents or hydroxyl; unsubstituted phenyl; phenyl substituted with1, 2 or 3 substituents independently selected from the group consistingof halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, C₁₋₃alkyl substituted with one ormore independently selected halo substituents, cyano, hydroxyl, amino,carboxyl, C₁₋₃ alkyloxy-C₁₋₃ alkyl, C₁₋₃alkyloxy, C₁₋₃alkyloxysubstituted with one or more independently selected halo substituents,C₁₋₃alkylcarbonyl, mono- and di(C₁₋₃alkyl)amino, and morpholinyl;unsubstituted (phenyl)C₁₋₃ alkyl; (phenyl)C₁₋₃ alkyl wherein the phenyland the C₁₋₃alkyl part of the substituent may each be independentlysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl, C₁₋₃alkylsubstituted with one or more independently selected halo substituents,cyano, hydroxyl, amino, carboxyl, C₁₋₃ alkyloxyC₁₋₃ alkyl, C₁₋₃alkyloxy, C₁₋₃ alkyloxy substituted with one or more independentlyselected halo substituents, C₁₋₃ alkylcarbonyl, mono- or di(C₁₋₃alkyl)amino, morpholinyl and (C₃₋₇cyclo alkyl)C₁₋₃ alkyloxy;unsubstituted phenyloxy; phenyloxy substituted with 1, 2 or 3substituents independently selected from the group consisting of halo,C₁₋₃alkyl, C₁₋₃alkyl substituted with one or more independently selectedhalo substituents, C₁₋₃ alkyloxy, and C₁₋₃ alkyloxy substituted with oneor more independently selected halo substituents; unsubstitutedphenyloxy(C₁₋₃ alkyl)oxy; unsubstituted (phenylC₁₋₃ alkyl)oxy;phenyl(C₁₋₃ alkyl)oxy wherein the phenyl part of the substituent issubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halo, C₁₋₃alkyl, C₁₋₃alkyl substituted with one ormore independently selected halo substituents, C₁₋₃ alkyloxy, and C₁₋₃alkyloxy substituted with one or more independently selected halosubstituents; unsubstituted phenyloxyC₁₋₃ alkyl; (phenyloxy)C₁₋₃alkylsubstituted with 1 or 2 substituents independently selected from thegroup consisting of halo, C₁₋₃alkyl, C₁₋₃alkyl substituted with one ormore independently selected halo substituents, C₁₋₃ alkyloxy, and C₁₋₃alkyloxy substituted with one or more independently selected halosubstituents; unsubstituted phenylamino; phenylamino substituted with 1or 2 independently selected halo substituents; (phenylC₁₋₃ alkyl)amino;(phenylamino)(C₁₋₃ alkyl); (C₃₋₇cycloalkyl)C₁₋₃ alkyl;[phenyl(C₃₋₇cycloalkyl)]C₁₋₃ alkyl; Het¹; Het²; Het²oxy; Het²-methyloxy;Het³; and phenyl with two vicinal substituents which taken together forma bivalent radical of formula—N═CH—NH—  (a),—CH═CH—NH—  (b), or—O—CH₂—CH₂—NH—  (c); R^(4a) is selected from the group consisting ofhydrogen; halogen; trifluoromethyl; trifluoromethoxy; hydroxyl;C₁₋₃alkyl; C₁₋₃alkyloxy; hydroxyC₁₋₃alkyl; hydroxyl-C₁₋₃ alkyloxy;fluoroC₁₋₃ alkyl; fluoroC₁₋₃ alkyloxy; cyano; unsubstituted phenyl; andphenyl substituted with 1 or 2 substituents independently selected fromthe group consisting of halo, C₁₋₃ alkyloxy, hydroxyC₁₋₃ alkyl,trifluoromethyl and trifluoromethoxy; or CR^(3a)R^(4a) forms a radicalof formula (d), (e), (f), (g) or (h);

wherein each W^(1d), W^(1e), W^(2e) and W^(1f) is independently selectedfrom CH and N; each R^(7d), R^(7e), R^(7f), R^(7g), R^(8d), R^(8e),R^(8f), R^(8g) is independently selected from hydrogen, methyl andfluoro; or each CR^(7d)R^(8d), CR^(7e)R^(8e), CR^(7f)R^(8f),CR^(7g)R^(8g) form a carbonyl group; each R^(9d), R^(9e), R^(9f), andR^(9g) is fluoro; each q1, q2, q3 or q4 is independently selected from0, 1 and 2; r is 0 or 1; s is 0 or 1; each R^(3b) and R^(3c) is selectedfrom the group consisting of C₁₋₃alkyl; C₁₋₃alkyl substituted with oneor more independently selected halo substituents; unsubstituted phenyl;phenyl substituted with 1, 2 or 3 substituents independently selectedfrom the group consisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃alkyl,C₁₋₃alkyl substituted with one or more independently selected halosubstituents, cyano, hydroxyl, amino, carboxyl, C₁₋₃alkyloxyC₁₋₃alkyl,C₁₋₃alkyloxy, C₁₋₃alkyloxy substituted with one or more independentlyselected halo substituents, C₁₋₃alkylcarbonyl, mono- anddi(C₁₋₃alkyl)amino, and morpholinyl; unsubstituted (phenyl)C₁₋₃alkyl;(phenyl)-C₁₋₃alkyl wherein the phenyl and the C₁₋₃alkyl part of thesubstituent may each be independently substituted with 1, 2 or 3substituents independently selected from the group consisting of halo,C₁₋₃alkyl, hydroxyC₁₋₃alkyl, C₁₋₃alkyl substituted with one or moreindependently selected halo substituents, cyano, hydroxyl, amino,carboxyl, C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃alkyloxy, C₁₋₃alkyloxy substitutedwith one or more independently selected halo substituents,C₁₋₃alkylcarbonyl, mono- or di(C₁₋₃alkyl)amino, morpholinyl,C₃₋₇cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₃ alkyl, and(C₃₋₇cycloalkyl)-C₁₋₃alkyloxy; unsubstituted (phenyloxy)C₁₋₃ alkyl;(phenyloxy)-C₁₋₃ alkyl substituted with 1 or 2 substituentsindependently selected from the group consisting of halo, C₁₋₃alkyl,C₁₋₃alkyl substituted with one or more independently selected halosubstituents, C₁₋₃alkyloxy, and C₁₋₃alkyloxy substituted with one ormore independently selected halo substituents; (phenylamino)(C₁₋₃alkyl); phenyl with two vicinal substituents which taken together form abivalent radical of formula (a), (b) or (c) as previously defined; Het¹;Het²; Het³; unsubstituted C₃₋₇cycloalkyl; C₃₋₇cycloalkyl substitutedwith 1 or 2 substituents independently selected from C₁₋₃alkyl,C₁₋₃alkyl substituted with one or more independently selected halosubstituents, or hydroxyl; (C₃₋₇cycloalkyl)C₁₋₃alkyl; and[phenyl-(C₃₋₇cycloalkyl)]C₁₋₃ alkyl; R^(3d) and R^(4d) are eachindependently selected from the group consisting of hydrogen and C₁₋₃alkyl; each R^(5a), R^(5b), R^(5c), R^(5d), R^(6a), R^(6b), R^(6c) andR^(6d) is independently selected from the group consisting of hydrogenand C₁₋₃alkyl; or each pair R^(5a)R^(6a), R^(5b)R^(6b), R^(5c)R^(6c),R^(5d)R^(6d) are substituents on the same carbon atom and eachCR^(5a)R^(6a), CR^(5b)R^(6b), CR^(5c)R^(6c), CR^(5d)R^(6d) together forma (C═O) or a C₃₋₇cycloalkylidene radical; each R^(10a), R^(10b) andR^(10c) is selected from H, C₁₋₃alkyl and C₁₋₃alkyloxy; wherein, in(L-e), when t is 1 or 2, R¹¹ is hydrogen and R¹² is selected from asubstituent selected from the group consisting of phenyl, phenyloxy andphenylamino, each of which may be optionally substituted with 1 or 2halo substituents; or when t is 1 or 3, then CR¹¹R¹² form a radical offormula (i) or formula (j)

wherein each R^(13i) and R^(13j) is independently selected from methyland trifluoromethyl; each R^(14i) or R^(14j) is fluoro; each u1 and u2is independently 0, 1 or 2; v1 is selected from the group of 0, 1 and 2;v2 is selected from the group of 1 and 2; each z1 and z2 isindependently selected from the group of 0, 1 and 2; each k1 and k2 isindependently selected from the group of 0, 1 and 2; wherein, in (L-f) wis 1 or 2; wherein in (L-g) Z is CR¹⁶R¹⁷ and R¹⁵ is hydrogen when each xis 0 and y is 1; or Z is CR¹⁶R¹⁷ and R¹⁵ is selected from the groupconsisting of hydrogen, methyl and phenyl when each x is 0 and y is 2;or Z is NR¹⁶ when each x is 1 and y is 1; wherein R¹⁶ and R¹⁷ are eachindependently selected from the group consisting of hydrogen;unsubstituted phenyl; and phenyl substituted with 1, 2 or 3 halosubstituents; wherein in (L-h), Q is O or N—R¹⁸, wherein R¹⁸ is selectedfrom hydrogen and C₁₋₃alkyl; wherein each Het¹ is a saturatedheterocyclic radical selected from pyrrolidinyl; piperidinyl;piperazinyl; and morpholinyl; each of which may be optionallysubstituted with 1 or 2 substituents independently selected from thegroup consisting of C₁₋₆alkyl, halo, C₁₋₃alkyl substituted with one ormore independently selected halo substituents, unsubstituted phenyl orphenyl substituted with 1, 2 or 3 substituents independently selectedfrom the group consisting of halo, trifluoromethyl, andtrifluoromethoxy; and each Het² is an aromatic heterocyclic radicalselected from pyridinyl and pyrimidinyl; each of which is unsubstitutedor substituted with 1 or 2 substituents selected from the groupconsisting of halo; C₁₋₃ alkyl; C₁₋₃ alkyloxy; and C₁₋₃ alkylsubstituted with one or more independently selected halo substituents;each Het³ is a heterocyclic radical selected from 1,3-thiazolyloptionally substituted with C₁₋₃ alkyl; unsubstituted benzofuranyl;unsubstituted 3,4-dihydro-2H-chromenyl; and unsubstituted 1H-indolyl;each halo is selected from the group consisting of fluoro, chloro, bromoand iodo; or a pharmaceutically acceptable salt or a solvate thereof. 2.The compound of formula (I) according to claim 1, or a stereochemicallyisomeric form thereof, wherein n is selected from 0 and 1; m is selectedfrom 0 and 1; R is methyl; R¹ is selected from the group consisting ofC₁₋₆alkyl; (C₁₋₃alkyloxy)C₁₋₃alkyl; [(C₁₋₃ alkyloxy)-C₁₋₃ alkyloxy]C₁₋₃alkyl; C₁₋₃ alkyl substituted with one or more halo substituents;unsubstituted phenyl; (benzyloxy)C₁₋₃ alkyl; unsubstitutedC₃₋₇cycloalkyl; C₃₋₇cycloalkyl substituted with C₁₋₃alkyl substitutedwith one or more halo substituents; (C₃₋₇cycloalkyl)C₁₋₃ alkyl;[(C₃₋₇cycloalkyl)C₁₋₃ alkyloxy]-C₁₋₃ alkyl;(C₃₋₇cycloalkyl)C₁₋₃alkyloxy; Het¹C₁₋₃alkyl; Het²; and Het²C₁₋₃alkyl; R²is selected from the group consisting of cyano; halo; C₁₋₃alkylsubstituted with one or more halo substituents; C₁₋₃ alkyl; andC₃₋₇cycloalkyl;

is an N-containing heterocycle selected from the group consisting of(L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L-h); whereinR^(3a) is selected from the group consisting of C₁₋₃alkyl substitutedwith one or more halo substituents; unsubstituted phenyl; phenylsubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of halo, hydroxyC₁₋₃alkyl, C₁₋₃alkyl substituted withone or more halo substituents, hydroxyl, and C₁₋₃alkyloxy; phenyloxysubstituted with 1 or 2 independently selected halo substituents;phenyl(C₁₋₃alkyl)oxy wherein the phenyl part of the substituent issubstituted with 1, 2, or 3 independently selected halo substituents;(phenyloxy)C₁₋₃alkyl wherein the phenyl part of the substituent issubstituted with 1 or 2 halo substituents; unsubstituted phenylamino;phenylamino substituted with 1 or 2 halo substituents;(phenylC₁₋₃alkyl)amino; Het¹; Het²; Het²oxy; Het²-methyloxy; and Het³;R^(4a) is selected from the group consisting of hydrogen; halogen;trifluoromethyl; C₁₋₃ alkyl; C₁₋₃ alkyloxy; and unsubstituted phenyl; orCR^(3a)R^(4a) forms a radical of formula (d), (e), (f), (g) or (h);wherein each W^(1d), W^(1e), W^(2e) and W^(1f) is independently selectedfrom CH and N; each R^(7d), R^(7e), R^(7f), R^(7g), R^(8d), R^(8e),R^(8f), R^(8g) is independently selected from hydrogen, methyl andfluoro; or each CR^(7d)R^(8d), CR^(7g)R^(8g) form a carbonyl group; eachR^(9d), R^(9e), R^(9f), and R^(9g) is fluoro; each q1, q2, q3 or q4 isindependently selected from 0, 1 and 2; r is 0 or 1; s is 0 or 1; eachR^(3b) and R^(3c) is selected from the group consisting of C₁₋₃alkylsubstituted with one or more halo substituents; unsubstituted phenyl;phenyl substituted with 1, 2 or 3 substituents independently selectedfrom the group consisting of halo, C₁₋₃alkyloxy and C₁₋₃alkylsubstituted with one or more halo substituents; unsubstituted(phenyl)C₁₋₃ alkyl; (phenyl)C₁₋₃ alkyl wherein the phenyl and the C₁₋₃alkyl parts of the substituent may each be independently substitutedwith 1, 2 or 3 substituents independently selected from the groupconsisting of halo, C₁₋₃alkyl, C₁₋₃alkyl substituted with one or morehalo substituents, and (C₃₋₇cycloalkyl)-C₁₋₃alkyloxy; Het²; Het³;C₃₋₇cycloalkyl substituted with 1 or 2 substituents independentlyselected from the group consisting of C₁₋₃ alkyl, C₁₋₃alkyl substitutedwith one or more halo substituents, and hydroxyl; and [phenyl(C₃₋₇cycloalkyl)]C₁₋₃ alkyl; each R^(3d) and R^(4d) is independently selected fromhydrogen and C₁₋₃alkyl; each R^(5a), R^(5b), R^(5c); R^(5d), R^(6a),R^(6b), R^(6c) and R^(6d) is independently selected from the groupconsisting of hydrogen and C₁₋₃alkyl; or CR^(5b)R^(6b) together form a(C═O) or a C₃₋₇cycloalkylidene radical; each R^(10a), R^(10b) andR^(10c) is H; wherein, in (L-e), when t is 1 or 2, R¹¹ is hydrogen andR¹² is selected from a substituent selected from the group consisting ofphenyl, phenyloxy and phenylamino, each of which may be optionallysubstituted with 1 or 2 halo substituents; or when t is 1, then CR¹¹R¹²form a radical of formula (i); wherein R^(14i) is fluoro; u1 is 0 or 1;v1 is 2; z1 is selected from the group of 1 and 2; k1 is 0; or when t is3, then CR¹¹R¹² form a radical of formula (i); wherein R^(14i) isfluoro; u1 is 0 or 1; v1 is 0; z1 is selected from the group of 1 and 2;k1 is 0; wherein, in (L-f) w is 1 or 2; wherein in (L-g) Z is CR¹⁶R¹⁷and R¹⁵ is hydrogen when each x is 0 and y is 1; or Z is CR¹⁶R¹⁷ and R¹⁵is phenyl when each x is 0 and y is 2; or Z is NR¹⁶ when each x is 1 andy is 1; wherein R¹⁶ and R¹⁷ are each independently selected from thegroup consisting of hydrogen; unsubstituted phenyl; and phenylsubstituted with 1, 2 or 3 halo substituents; wherein in (L-h), Q is O;each Het¹ is a saturated heterocyclic radical selected frompyrrolidinyl; piperidinyl; piperazinyl; and morpholinyl; each of whichis unsubstitued or substituted with 1 or 2 substituents independentlyselected from the group consisting of fluoro, C₁₋₃alkyl substituted withone or more halo substituents, and unsubstituted phenyl; and each Het²is an aromatic heterocyclic radical selected from pyridinyl andpyrimidinyl; each of which is unsubstituted or substituted with 1 or 2substituents independently selected from the group consisting of halo;C₁₋₃ alkyl; and C₁₋₃ alkyloxy; each Het³ is a heterocyclic radicalselected from 1,3-thiazolyl optionally substituted with C₁₋₃ alkyl;unsubstituted benzofuranyl; unsubstituted 3,4-dihydro-2H-chromenyl; andunsubstituted 1H-indolyl; each halo is selected from the groupconsisting of fluoro, chloro, and bromo; or a pharmaceuticallyacceptable salt or a solvate thereof.
 3. The compound according to claim1, or a stereochemically isomeric form thereof, wherein n is selectedfrom 0 or 1; m is 0 or 1; R is methyl; R¹ is selected from the groupconsisting of C₁₋₆alkyl; C₁₋₃alkyl substituted with one or moreindependently selected halo substituents; and (C₃₋₇cycloalkyl)C₁₋₃alkyl; R² is selected from halo, C₁₋₃alkyl, and C₁₋₃alkyl substitutedwith one or more independently selected halo substituents;

is selected from (L-a) and (L-b); wherein R^(3a) is selected from thegroup consisting of unsubstituted phenyl; phenyl substituted with 1 or 2independently selected halo substituents; pyridinyl; and pyrimidinyl;R^(4a) is selected from hydrogen; halo and C₁₋₃alkyl; or CR^(3a)R^(4a)forms a radical of formula (d); wherein W^(1d) is CH; R^(7d) and R^(8d)are both methyl; R^(9d) is fluoro; q1 is 1; R^(3b) is phenyl substitutedwith 1 or 2 halo substituents; R^(5a), R^(5b), R^(6a) and R^(6b) arehydrogen; and R^(10a) and R^(10b) are hydrogen; halo is fluoro orchloro; or a pharmaceutically acceptable salt or a solvate thereof. 4.The compound according to claim 1 or a stereochemically isomeric formthereof wherein m is 0;

is selected from the group consisting of (L-a′) and (L-b′)

R¹ is selected from hydrogen; C₁₋₆alkyl; (C₁₋₃alkyloxy)C₁₋₃alkyl;[(C₁₋₃alkyloxy)-C₁₋₃alkyloxy]C₁₋₃alkyl; mono-, di- or tri-haloC₁₋₃alkyl;unsubstituted benzyl; benzyl substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halo, C₁₋₃ alkyl,C₁₋₃ alkyloxy, C₁₋₃ alkyloxyC₁₋₃ alkyl, hydroxyC₁₋₃ alkyl, cyano,hydroxyl, amino, C(═O)R′, C(═O)OR′, C(═O)NR′R″, mono- ordi(C₁₋₃alkyl)amino, morpholinyl, (C₃₋₇cycloalkyl)C₁₋₃alkyloxy,trifluoromethyl and trifluoromethoxy, wherein R′ and R″ areindependently selected from hydrogen and C₁₋₆alkyl; (benzyloxy)C₁₋₃alkyl; unsubstituted C₃₋₇cycloalkyl; C₃₋₇cycloalkyl substituted withtrihaloC₁₋₃ alkyl; (C₃₋₇cycloalkyl)C₁₋₃ alkyl;4-(2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine)methyl; Het¹;Het¹C₁₋₃alkyl; Het² and Het²C₁₋₃alkyl; R² is selected from cyano; halo;mono-, di- or tri-haloC₁₋₃alkyl; mono-, di- and tri-haloC₁₋₃alkyloxy;C₁₋₃alkyl; C₃₋₇cycloalkyl; and (C₃₋₇cycloalkyl)C₁₋₃alkyl; R^(3a) andR^(3b) are each selected from unsubstituted phenyl; phenyl substitutedwith 1, 2 or 3 substituents independently selected from the groupconsisting of halo, C₁₋₃alkyl, hydroxyC₁₋₃ alkyl, mono-, di- andtri-haloC₁₋₃ alkyl, cyano, hydroxyl, amino, carboxyl, C₁₋₃alkyloxyC₁₋₃alkyl, C₁₋₃ alkyloxy, mono-, di- or tri-haloC₁₋₃ alkyloxy, C₁₋₃alkylcarbonyl, mono- and di(C₁₋₃ alkyl)amino, and morpholinyl;unsubstituted benzyl; benzyl substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halo, C₁₋₃ alkyl,hydroxyC₁₋₃ alkyl, mono-, di- or tri-haloC₁₋₃ alkyl, cyano, hydroxyl,amino, carboxyl, C₁₋₃ alkyloxyC₁₋₃ alkyl, C₁₋₃ alkyloxy, mono-, di- andtri-haloC₁₋₃ alkyloxy, C₁₋₃ alkylcarbonyl, mono- or di(C₁₋₃ alkyl)amino,morpholinyl and (C₃₋₇cycloalkyl)C₁₋₃alkyloxy; phenyl with two vicinalsubstituents which taken together form a bivalent radical of formula—N═CH—NH—  (a),—CH═CH—NH—  (b), or—O—CH₂—CH₂—NH—  (c); morpholinyl; pyridinyl; pyrimidinyl; pyridinyloxysubstituted with 1 or 2 C₁₋₃alkyl groups; unsubstituted C₃₋₇cycloalkylor C₃₋₇cycloalkyl substituted with 1 or 2 substituents independentlyselected from C₁₋₃ alkyl, trihaloC₁₋₃ alkyl or hydroxyl; R^(4a) isselected from hydrogen; halogen; trifluoromethyl; trifluoromethoxy;hydroxyl; C₁₋₃alkyl; C₁₋₃ alkyloxy; hydroxyC₁₋₃ alkyl; hydroxyl-C₁₋₃alkyloxy; fluoroC₁₋₃ alkyl; fluoroC₁₋₃alkyloxy; cyano; unsubstitutedphenyl; or phenyl substituted with 1 or 2 substituents independentlyselected from the group consisting of halo, C₁₋₃alkyloxy,hydroxyC₁₋₃alkyl, trifluoromethyl and trifluoromethoxy; orR^(3a)—C—R^(4a) together represent a radical of formula (d′) or (e′) or(f′) or (g′)

wherein W^(1d), W^(1e) and W^(1f) are each selected from CH or N;R^(7d), R^(7e), R^(7f), R^(8d), R^(8e) and R^(8f) are each independentlyselected from hydrogen, methyl or fluoro; R^(9d), R^(9e) and R^(9f) areeach selected from hydrogen or fluoro; R^(5a), R^(5b), R^(6a) and R^(6b)are each independently selected from the group of hydrogen and C₁₋₃alkylor CR^(5a)R^(6a) and CR^(5b)R^(6b) together form a C₃₋₇cycloalkylradical; n is 0 or 1; wherein each Het¹ is a saturated heterocyclicradical selected from pyrrolidinyl; piperidinyl; piperazinyl; andmorpholinyl; each of which may be optionally substituted with 1 or 2substituents independently selected from the group consisting ofC₁₋₆alkyl, mono-, di- or tri-haloC₁₋₃alkyl, unsubstituted phenyl andphenyl substituted with 1, 2 or 3 substituents independently selectedfrom the group consisting of halo, trifluoromethyl, andtrifluoromethoxy; and each Het² is an aromatic heterocyclic radicalselected from unsubstituted pyridinyl and pyrimidinyl; or apharmaceutically acceptable salt or a solvate thereof.
 5. The compoundaccording to claim 1, including any stereochemically isomeric formthereof, wherein said compound is selected from the group consisting of:8-chloro-7-(4-fluoro-4-phenyl-1-piperidinyl)-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo-[4,3-a]pyridine;3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine;3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine.1.1HCl;1′-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-5-fluoro-3,3-dimethyl-spiro[isobenzofuran-1(3H),4′-piperidine],3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine.1.8HCl,3-(cyclopropylmethyl)-7-[(4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,8-chloro-3-(cyclopropylmethyl)-7-[[4-(2,4-difluorophenyl)-1-piperazinyl]methyl]-1,2,4-triazolo[4,3-a]pyridine,3-(cyclopropylmethyl)-7-[[4-(4-fluorophenyl)-4-methyl-1-piperidinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,and3-(cyclopropylmethyl)-7-[(4-fluoro-4-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,or a pharmaceutically acceptable salt thereof or a solvate thereof. 6.The compound according to claim 1, including any stereochemicallyisomeric form thereof, wherein said compound is selected from3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine;and3-(cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl)-1,2,4-triazolo-[4,3-a]pyridine.1.1HCl;or a pharmaceutically acceptable salt thereof or a solvate thereof.
 7. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 and a pharmaceutically acceptable carrier orexcipient.
 8. A compound of claim 1 for use as a medicament.
 9. Acompound of claim 1 for use in the treatment or prevention of a centralnervous system disorder selected from the group of anxiety disorders,psychotic disorders, personality disorders, substance-related disorders,eating disorders, mood disorders, migraine, epilepsy or convulsivedisorders, childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia.
 10. The compound according to claim 9, foruse in the treatment or prevention of a central nervous system disorderselected from the group of anxiety, schizophrenia, migraine, depression,epilepsy, behavioral and psychological symptoms of dementia, majordepressive disorder, treatment resistant depression, bipolar depression,generalised anxiety disorder, post-traumatic stress disorder, bipolarmania, substance abuse and mixed anxiety and depression.
 11. A compoundof claim 1 in combination with an orthosteric agonist of mGluR2 for usein the treatment or prevention of a central nervous system disorderselected from the group of anxiety disorders, psychotic disorders,personality disorders, substance-related disorders, eating disorders,mood disorders, migraine, epilepsy or convulsive disorders, childhooddisorders, cognitive disorders, neurodegeneration, neurotoxicity andischemia.
 12. A process for preparing a pharmaceutical composition,characterized in that a pharmaceutically acceptable carrier isintimately mixed with a therapeutically effective amount of a compoundof claim
 1. 13. A product comprising (a) a compound of claim 1; and (b)an mGluR2 orthosteric agonist, as a combined preparation forsimultaneous, separate or sequential use in the treatment or preventionof a central nervous system disorder selected from the group of anxietydisorders, psychotic disorders, personality disorders, substance-relateddisorders, eating disorders, mood disorders, migraine, epilepsy orconvulsive disorders, childhood disorders, cognitive disorders,neurodegeneration, neurotoxicity and ischemia.
 14. A method of treatingor preventing a central nervous system disorder selected from the groupof anxiety disorders, psychotic disorders, personality disorders,substance-related disorders, eating disorders, mood disorders, migraine,epilepsy or convulsive disorders, childhood disorders, cognitivedisorders, neurodegeneration, neurotoxicity and ischemia comprisingadministering to a subject in need thereof a compound of claim
 1. 15. Acompound of claim 1 in combination with an orthosteric agonist of mGluR2for use in the treatment or prevention of a central nervous systemdisorder selected from the group of anxiety, schizophrenia, migraine,depression, epilepsy, behavioral and psychological symptoms of dementia,major depressive disorder, treatment resistant depression, bipolardepression, generalised anxiety disorder, post-traumatic stressdisorder, bipolar mania, substance abuse and mixed anxiety anddepression.